Melanocortin receptor agonists

ABSTRACT

The present invention relates to melanocortin receptor agonist of the formula I useful in the treatment of obesity, diabetes, and male and/or female sexual dysfunction

[0001] The present invention relates to melanocortin receptor agonists,and as such is useful in the treatment of disorders responsive to theactivation of melanocortin receptors, such as obesity, diabetes, andmale and/or female sexual dysfunction.

[0002] Pro-opiomelanocortin (POMC) derived peptides are known to affectfood intake. Several lines of evidence support the notion that theG-protein coupled receptors (GPCRs) of the melanocortin receptor (MC-R)family, several of which are expressed in the brain, are targets of POMCderived peptides involved in the control of food intake and metabolism.

[0003] Evidence for the involvement of MC-R in obesity includes: i) theagouti (A^(vy)) mouse which ectopically expresses an antagonist of theMC-1R, -3R and -4R is obese, indicating that blocking the action ofthese three MC-Rs can lead to hyperphagia and metabolic disorders; ii)MC-4R knockout mice (Huszar et al., Cell, 88:131-141, 1997) recapitulatethe phenotype of the agouti mouse and these mice are obese; iii) thecyclic heptapeptide MC-1R, -3R, -4R, and -5R agonist melanotanin-II(MT-II) injected intracerebroventricularly (ICV) in rodents, reducesfood intake in several animal feeding models (NPY, ob/ob, agouti,fasted) while ICV injected SHU-9119 (MC-3R, -4R antagonist; MC-1R and-5R agonist) reverses this effect and can induce hyperphagia; iv)chronic intraperitoneal treatment of Zucker fatty rats with an α-NDP-MSHderivative (HP228) has been reported to activate MC-1R, -3R, -4R and 5Rand to attenuate food intake and body weight gain over a 12 week period.

[0004] Five MC-Rs have thus far been identified, and these are expressedin different tissues. MC-1R was initially characterized by dominant gainof function mutations at the extension locus, affecting coat-color bycontrolling phaeomelanin to eumelanin conversion through control oftyrosinase. MC-1R is mainly expressed in melanocytes. MC-2R is expressedin the adrenal gland and represents the ACTH receptor. MC-3R isexpressed in the brain, gut and placenta and may be involved in thecontrol of food intake and thermogenesis. MC-4R is uniquely expressed inthe brain and its inactivation was shown to cause obesity. MC-5R isexpressed in many tissues including white fat, placenta and exocrineglands. A low level of expression is also observed in the brain. MC-5Rknock out mice reveal reduced sebaceous gland lipid production (Chen etal., Cell, 91:789-798, 1997).

[0005] Evidence for the involvement of MC-R in male and/or female sexualdisfunction is detailed in WO 00/74670.

[0006] Melanocortin receptor agonist compounds were disclosed in WO99/64002.

[0007] The present invention relates to compound of formula I:

[0008] or a pharmaceutically acceptable salt, solvate or stereoisomerthereof, wherein

[0009] L and L¹ are both hydrogen, or combine together to form an oxogroup;

[0010] R² is:

[0011] Hydrogen, C₁-C₈ alkyl, CONHC₁-C₄ alkyl, (D)phenyl, oxo, or (D)C₃-C₇ cycloalkyl, provided that when R² is oxo, R² is on one of the ringcarbon atoms adjacent to Q bearing nitrogen atom;

[0012] R³ is: phenyl, aryl or thienyl;

[0013] wherein phenyl, aryl and thienyl are optionally substituted withone to three substituents independently selected from the groupconsisting of:

[0014] cyano, perfluoroalkoxy, halo, C₁-C₈ alkyl, (D)C₃-C₇ cycloalkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl;

[0015] R⁴ is hydrogen, C₁-C₈ alkyl, C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl, or(D)phenyl;

[0016] Q is: —C(R^(a1)) (R^(a2)) (R^(a3))

[0017] Wherein R^(a1) is C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl,C₃-C₈ alkoxy, (D)C₃-C₇ cycloalkyl, heterocyclic, alkylheterocyclic,(D)phenyl, aryl, 5 to 7 member benzofused bicyclic ring, or heteroaryl,and wherein C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, (D)C₃-C₇cycloalkyl, heterocyclic, alkylheterocyclic, phenyl, aryl, 5- or7-membered benzofused bicyclic ring, and heteroaryl, are each optionallysubstituted with one to five substituents independently selected from R;

[0018] R is:

[0019] hydroxy,

[0020] halo,

[0021] C₁-C₈ alkyl,

[0022] C₂-C₈ alkenyl,

[0023] C_(l)-C₈ alkoxy,

[0024] C₁-C₄ haloalkyl,

[0025] (D)C₃-C₇ cycloalkyl,

[0026] (D)aryl,

[0027] (D)heteroaryl;

[0028] (D)C(O)C₁-C₄ alkyl,

[0029] (D)C(O)OC₁-C₄ alkyl,

[0030] (D)C(O)heteroaryl,

[0031] (CH₂)_(m)N(R⁸)₂,

[0032] (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl,

[0033] (CH₂)_(m)NR⁸SO₂(C₁-C₄ alkyl),

[0034] (D)OC₁-C₄ alkyl,

[0035] (D)OC(O)C₁-C₄ alkyl,

[0036] (D)heterocyclic,

[0037] (D)SC₁-C₄ alkyl, or

[0038] (D)SO₂N(R⁸ )₂;

[0039] wherein C₁-C₈ alkyl, C₁-C₈ alkoxy, C₃-C₇ cycloalkyl, phenyl,aryl, heterocyclic, and heteroaryl are optionally substituted with oneto five substituents independently selected from R⁸; and provided thatwhen R is halo or hydroxy it is not substituted on a carbon adjacent toa heteroatom;

[0040] R^(a2) is

[0041] C₁-C₈ alkyl,

[0042] C₂-C₈ alkenyl,

[0043] C₂-C₈ alkynyl,

[0044] (D)C₃-C₇ cycloalkyl,

[0045] phenyl,

[0046] aryl,

[0047] (CH₂)_(m)N(R⁸)₂,

[0048] (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl,

[0049] (CH₂)_(m)NR⁸C(O)O C₁-C₄ alkyl,

[0050] (CH₂)_(m)NR⁸SO₂(C₁-C₄ alkyl),

[0051] (CH₂)_(m)OC₁-C₄ alkyl,

[0052] (CH₂)_(m)OC(O)C₁-C₄ alkyl,

[0053] CON(R⁸)₂,

[0054] wherein for the group or subgroup —N(R⁸)₂, each R⁸ may combinewith the other to form a 5, 6, or 7-membered saturated or unsaturated,optionally substituted nitrogen containing heterocycle;

[0055] R^(a3) is selected from the group consisting of hydrogen, methyl,ethyl and propyl;

[0056] each R⁸ is independently:

[0057] hydrogen,

[0058] oxo,

[0059] C₁-C₈ alkyl,

[0060] C₂-C₈ alkenyl,

[0061] (D)C₃-C₇ cycloalkyl,

[0062] phenyl,

[0063] aryl or

[0064] heteroaryl,

[0065] wherein C₁-C₈ alkyl, C₁-C₈ alkenyl, C₃-C₇ cycloalkyl, phenyl,aryl and heteroaryl are optionally substituted with one to threesubstituents selected from the group consisting of C₁-C₈ alkyl, halo,and hydroxy; provided that the halo and hydroxy groups are notsubstituted on a carbon adjacent to a heteroatom;

[0066] T is:

[0067] R¹⁰ is hydrogen, (C₁-C₈) alkyl, C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl,C₂-C₈ alkynyl, phenyl, aryl, or heteroaryl;

[0068] R¹¹ is independently hydrogen, (C₁-C₈) alkyl, or (D)phenyl, oraryl;

[0069] R¹² is independently:

[0070] C₁-C₈ alkyl,

[0071] phenyl,

[0072] aryl,

[0073] heteroaryl,

[0074] (CH₂)_(n)N(R⁸ )₂,

[0075] (CH₂)_(n)NR⁸C(O)C₁-C₄ alkyl,

[0076] (CH₂)_(n)NR⁸C(O)OC₁-C₄ alkyl,

[0077] (CH₂)_(n)[O]_(q)(CH₂)_(n)N(R⁸)₂,

[0078] (CH₂)_(n)[O]_(q)(CH₂)_(n)NR⁸C(O)C₁-C₄ alkyl,

[0079] (CH₂)_(n)[O]_(q)(CH₂)_(n)NR⁸SO₂(C₁-C₄ alkyl),

[0080] (CH₂)_(n)[O]_(q)-heterocyclic,

[0081] (CH₂)_(n)[O]_(q)(C₁-C₈)alkyl-heterocyclic; and wherein for R¹²

[0082] n is 2-8;

[0083] R¹³ is independently:

[0084] hydrogen,

[0085] C₁-C₈ alkyl,

[0086] (D)C₃-C₇ cycloalkyl,

[0087] (D)phenyl,

[0088] C(O)C₁-C₈ alkyl,

[0089] SO₂C₁-C₈ alkyl, or

[0090] SO₂-phenyl;

[0091] D is a bond or C₁-C₄ alkyl;

[0092] y is 1 or 2;

[0093] m is 1-4;

[0094] n is 0-8;

[0095] p is 0-4; and

[0096] q is 0-1,

[0097] and wherein,

[0098] aryl is defined as benzylic or naphthyl;

[0099] heteroaryl is defined as a monocyclic or bicyclic aromatic ringof 5 to 10 carbon atoms containing from one to three heteroatomsselected from O, N, or S; and

[0100] heterocyclic is defined as a monocyclic, bicyclic, or tricyclicring of 5 to 14 carbon atoms which can be aromatic or nonaromatic andcontaining from one to three heteroatoms selected from N, O, or S.

[0101] The present invention also relates to a compound of formula II:

[0102] or a pharmaceutically acceptable salt, solvate or stereoisomerthereof, wherein

[0103] L and L¹ are both hydrogen, or combine together to form an oxogroup;

[0104] R¹ is selected from the group consisting of:

[0105] Hydrogen,

[0106] Halo,

[0107] C₁-C₈ alkyl,

[0108] C₁-C₄ haloalkyl

[0109] C₂-C₈ alkenyl,

[0110] C2-C8 alkynyl,

[0111] (D)C₃-C₇ cycloalkyl,

[0112] phenyl,

[0113] aryl,

[0114] (D)N(R⁸)₂,

[0115] (D)NR⁸C(O)C₁-C₄ alkyl,

[0116] (D)NR⁸C(O)OC₁-C₄ alkyl,

[0117] (D)OC₁-C₄ alkyl,

[0118] wherein for the group or subgroup —N(R⁸)₂, each R⁸ may combinewith the other to form a 5, 6, or 7-membered saturated or unsaturated,optionally substituted nitrogen containing heterocycle;

[0119] R² is:

[0120] Hydrogen, C₁-C₈ alkyl, CONHC₁-C₄ alkyl, (D)phenyl, oxo, or(D)C₃-C₇ cycloalkyl, provided that when R² is oxo, R² is on one of thering carbon atoms adjacent to the nitrogen atom bearing the groupCR^(a2);

[0121] R^(3′) is: phenyl, aryl; wherein phenyl, and aryl are eachoptionally substituted with one to three substituents independentlyselected from the group consisting of: cyano, halo, C₁-C₈ alkyl,(D)C₃-C₇ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl and perfluoroalkoxy;

[0122] R⁴ is hydrogen, C₁-C₈ alkyl, C₃-C₈ alkenyl, or (D)phenyl;

[0123] R^(a2) is:

[0124] C₁-C₈ alkyl,

[0125] C₂-C₈ alkenyl,

[0126] C₂-C₈ alkynyl,

[0127] (D)C₃-C₇ cycloalkyl,

[0128] phenyl,

[0129] aryl,

[0130] (CH₂)_(m)N(R⁸)₂,

[0131] (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl,

[0132] (CH₂)_(m)NR⁸C(O)OC₁-C₄ alkyl,

[0133] (CH₂)_(m)NR⁸SO₂(C₁-C₄ alkyl),

[0134] (CH₂)_(m)OC₁-C₄ alkyl,

[0135] (CH₂)_(m)OC(O)C₁-C₄ alkyl,

[0136] CON(R⁸)₂,

[0137] wherein for the group or subgroup —N(R⁸)₂, each R⁸ may combinewith the other to form a 4, 5, 6, or 7-membered saturated orunsaturated, optionally substituted nitrogen containing heterocycle;

[0138] R^(a3) is selected from the group consisting of hydrogen, methyl,ethyl and propyl;

[0139] T′ is:

[0140] R is:

[0141] hydroxy,

[0142] halo,

[0143] C₁-C₈ alkyl,

[0144] C₂-C₈ alkenyl,

[0145] C₁-C₈ alkoxy,

[0146] C₁-C₄ haloalkyl,

[0147] (D)C₃-C₇ cycloalkyl,

[0148] (D)aryl,

[0149] (D)heteroaryl;

[0150] (D)C(O)C₁-C₄ alkyl,

[0151] (D)C(O)OC₁-C₄ alkyl,

[0152] (D)C(O) heteroaryl,

[0153] (CH₂)_(m)N(R⁸)₂,

[0154] (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl,

[0155] (CH₂)_(m)NR⁸SO₂(C₁-C₄ alkyl),

[0156] (D)OC₁-C₄ alkyl,

[0157] (D)OC(O)C₁-C₄ alkyl,

[0158] (D)heterocyclic,

[0159] (D)SC₁-C₄ alkyl, or

[0160] (D)SO₂N (R⁸)₂;

[0161] wherein C₁-C₈ alkyl, C₁-C₈ alkoxy, C₃-C₇ cycloalkyl, phenyl,aryl, heterocyclic, and heteroaryl are optionally substituted with oneto five substituents independently selected from R⁸; and provided thatwhen R is halo or hydroxy it is not substituted on a carbon adjacent toa heteroatom;

[0162] each R⁸ is independently:

[0163] hydrogen,

[0164] oxo,

[0165] C₁-C₈ alkyl,

[0166] C₂-C₈ alkenyl,

[0167] (D)C₃-C₇ cycloalkyl,

[0168] phenyl,

[0169] aryl or

[0170] heteroaryl,

[0171] wherein C₁-C₈ alkyl, C₁-C₈ alkenyl, C₃-C₇ cycloalkyl, phenyl,aryl and heteroaryl are optionally substituted with one to threesubstituents selected from the group consisting of C₁-C₈ alkyl, halo,and hydroxy; provided that the halo and hydroxy groups are notsubstituted on a carbon adjacent to a heteroatom;

[0172] R¹⁰ is hydrogen, (C₁-C₈)alkyl, C₃-C₈ alkenyl,

[0173] C₂-C₈ alkynyl, phenyl, aryl, or heteroaryl;

[0174] R¹¹ is independently hydrogen, (C₁-C₈)alkyl, or phenyl, aryl;

[0175] R¹² is independently:

[0176] C₃-C₈ alkyl,

[0177] phenyl,

[0178] aryl,

[0179] heteroaryl,

[0180] (CH₂)_(n)N(R⁸)₂,

[0181] (CH₂)_(n)NR⁸C(O)C₁-C₄ alkyl,

[0182] (CH₂)_(n)NR⁸C(O)OC₁-C₄ alkyl,

[0183] (CH₂)_(n)[O]_(q)(CH₂)_(n)N(R⁸)₂,

[0184] (CH₂)_(n)[O]_(q)(CH₂)_(n)NR⁸C(O)C₁-C₄ alkyl,

[0185] (CH₂)_(n)[O]_(q)(CH₂)_(n)NR⁸SO₂(C₁-C₄ alkyl),

[0186] (CH₂)_(n)[O]_(q)-heterocyclic,

[0187] (CH₂)_(n)[O]_(q)(C₁-C₈)alkyl-heterocyclic; and wherein for R¹²

[0188] n is 2-8;

[0189] R¹³ is independently:

[0190] hydrogen,

[0191] C₁-C₈ alkyl,

[0192] (D)C₃-C₇ cycloalkyl,

[0193] (D)phenyl,

[0194] C(O)C₁-C₈ alkyl,

[0195] SO₂C₁-C₈ alkyl, or

[0196] SO₂-phenyl;

[0197] D is a bond or C₁-C₄ alkyl;

[0198] y is 1 or 2;

[0199] u is 0, 1, or 2;

[0200] m is 1-4;

[0201] n is 0-8;

[0202] p is 0-4; and

[0203] q is 0-1; and wherein,

[0204] aryl is defined as benzyl or naphthyl;

[0205] heteroaryl is defined as a monocyclic or bicyclic aromatic ringof 5 to 10 carbon atoms containing from one to three heteroatomsselected from O, N, or S; and

[0206] heterocyclic is defined as a monocyclic, bicyclid, or tricyclicring of 5 to 14 carbon atoms which can be aromatic or non-aromatic andcontaining from one to three heteroatoms selected from N, O or S.

[0207] Another aspect of the present invention relates to a method fortreating obesity or diabetes mellitus in a patient which comprisesadministering to said patient an effective amount of a compound offormula I or II, or a pharmaceutical salt, solvate, enantiomer orprodrug thereof, wherein said compound is an agonist of themelanocortin-4 receptor.

[0208] Another aspect of the present invention relates to a method fortreating male or female sexual dysfunction, including erectiledysfunction, which comprises administering to said male or female aneffective amount of a compound of formula I or II, or a pharmaceuticalsalt thereof, wherein said compound is an agonist of the melanocortin-4receptor.

[0209] In addition, the present invention relates to a compound offormula I or II for use in treating obesity or diabetes as well as acompound of formula I or II for use in male or female sexualdysfunction, including erectile dysfunction wherein said compound is anagonist of the melanocortin-4 receptor.

[0210] In addition, the present invention relates to a compound offormula I or II for use in treating obesity and/or diabetes in companionanimals i.e. dogs, cats and the like wherein said compound is an agonistof the melanocortin-4 receptor.

[0211] Yet another aspect of the present invention relates to apharmaceutical composition comprising a compound of formula I or II or apharmaceutically acceptable salt thereof, and a pharmaceutical carrier.

[0212] The present invention also relates to the use of a compound offormula I:

[0213] or a pharmaceutically acceptable salt, solvate or stereoisomerthereof, wherein

[0214] L and L¹ are both hydrogen, or combine together to form an oxogroup;

[0215] R² is:

[0216] Hydrogen, C₁-C₈ alkyl, CONHC₁-C₄ alkyl, (D)phenyl, oxo, or(D)C₃-C₇ cycloalkyl, provided that when R² is oxo, R² is on one of thering carbon atoms adjacent to Q bearing nitrogen atom;

[0217] R³ is: phenyl, aryl or thienyl;

[0218] wherein phenyl, aryl and thienyl are optionally substituted withone to three substituents independently selected from the groupconsisting of:

[0219] cyano, perfluoroalkoxy, halo, C₁-C₈ alkyl, (D)C₃-C₇ cycloalkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl;

[0220] R⁴ is hydrogen, C₁-C₈ alkyl, C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl, or(D)phenyl;

[0221] Q is: —C(R^(a1))(R^(a2))(R^(a3))

[0222] Wherein R^(a1) is C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl,C₃-C₈ alkoxy, (D)C₃-C₇ cycloalkyl, heterocyclic, alkylheterocyclic,(D)phenyl, aryl, 5 to 7 member benzofused bicyclic ring, or heteroaryl,and wherein C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, (D)C₃-C₇cycloalkyl, heterocyclic, alkylheterocyclic, phenyl, aryl, 5- or7-membered benzofused bicyclic ring, and heteroaryl, are each optionallysubstituted with one to five substituents independently selected from R;

[0223] R is:

[0224] hydroxy,

[0225] halo,

[0226] C₁-C₈ alkyl,

[0227] C₂-C₈ alkenyl,

[0228] C₁-C₈ alkoxy,

[0229] C₁-C₄ haloalkyl,

[0230] (D)C₃-C₇ cycloalkyl,

[0231] (D)aryl,

[0232] (D)heteroaryl;

[0233] (D)C(O)C₁-C₄ alkyl,

[0234] (D)C(O)OC₁-C₄ alkyl,

[0235] (D)C(O)heteroaryl,

[0236] (CH₂)_(m)N(R⁸)₂,

[0237] (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl,

[0238] (CH₂)_(m)NR⁸SO₂(C₁-C₄ alkyl),

[0239] (D)OC₁-C₄ alkyl,

[0240] (D)OC(O)C₁-C₄ alkyl,

[0241] (D)heterocyclic,

[0242] (D)SC₁-C₄ alkyl, or

[0243] (D)SO₂N(R⁸)₂;

[0244] wherein C₁-C₈ alkyl, C₁-C₈ alkoxy, C₃-C₇ cycloalkyl, phenyl,aryl, heterocyclic, and heteroaryl are optionally substituted with oneto five substituents independently selected from R⁸; and provided thatwhen R is halo or hydroxy it is not substituted on a carbon adjacent toa heteroatom;

[0245] R^(a2) is

[0246] C₁-C₈ alkyl,

[0247] C₂-C₈ alkenyl,

[0248] C₂-C₈ alkynyl,

[0249] (D)C₃-C₇ cycloalkyl,

[0250] phenyl,

[0251] aryl,

[0252] (CH₂)_(m)N(R⁸)₂,

[0253] (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl,

[0254] (CH₂)_(m)NR⁸C(O)OC₁-C₄ alkyl,

[0255] (CH₂)_(m)NR⁸SO₂(C₁-C₄ alkyl),

[0256] (CH₂)_(m)OC₁-C₄ alkyl,

[0257] (CH₂)_(m)OC(O)C₁-C₄ alkyl,

[0258] CON(R⁸)₂,

[0259] wherein for the group or subgroup —N(R⁸)₂, each R⁸ may combinewith the other to form a 5, 6, or 7-membered saturated or unsaturated,optionally substituted nitrogen containing heterocycle;

[0260] R^(a3) is selected from the group consisting of hydrogen, methyl,ethyl and propyl;

[0261] each R⁸ is independently:

[0262] hydrogen,

[0263] oxo,

[0264] C₁-C₈ alkyl,

[0265] C₂-C₈ alkenyl,

[0266] (D)C₃-C₇ cycloalkyl,

[0267] phenyl,

[0268] aryl or

[0269] heteroaryl,

[0270] wherein C₁-C₈ alkyl, C₁-C₈ alkenyl, C₃-C₇ cycloalkyl, phenyl,aryl and heteroaryl are optionally substituted with one to threesubstituents selected from the group consisting of C₁-C₈ alkyl, halo,and hydroxy; provided that the halo and hydroxy groups are notsubstituted on a carbon adjacent to a heteroatom;

[0271] T is:

[0272] R¹⁰ is hydrogen, (C₁-C₈) alkyl, C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl,C₂-C₈ alkynyl, phenyl, aryl, or heteroaryl;

[0273] R¹¹ is independently hydrogen, (C₁-C₈) alkyl, or (D)phenyl, oraryl;

[0274] R¹² is independently:

[0275] C₁-C₈ alkyl,

[0276] phenyl,

[0277] aryl,

[0278] heteroaryl,

[0279] (CH₂)_(n)N(R⁸)₂,

[0280] (CH₂)_(n)NR⁸C(O)C₁-C₄ alkyl,

[0281] (CH₂)_(n)NR⁸C(O)OC₁-C₄ alkyl,

[0282] (CH₂)_(n)[O]_(q)(CH₂)_(n)N(R⁸)₂,

[0283] (CH₂)_(n)[O]_(q)(CH₂)_(n)NR⁸C(O)C₁-C₄ alkyl,

[0284] (CH₂)_(n)[O]_(q)(CH₂)_(n)NR⁸ SO₂(C₁-C₄ alkyl),

[0285] (CH₂)_(n)[O]_(q)-heterocyclic,

[0286] (CH₂)_(n)[O]_(q)(C₁-C₈)alkyl-heterocyclic; and wherein for R¹²

[0287] n is 2-8;

[0288] R¹³ is independently:

[0289] hydrogen,

[0290] C₁-C₈ alkyl,

[0291] (D)C₃-C₇ cycloalkyl,

[0292] (D)phenyl,

[0293] C(O)C₁-C₈ alkyl,

[0294] SO₂C₁-C₈ alkyl, or

[0295] SO₂-phenyl;

[0296] D is a bond or C₁-C₄ alkyl;

[0297] y is 1 or 2;

[0298] m is 1-4;

[0299] n is 0-8;

[0300] p is 0-4; and

[0301] q is 0-1,

[0302] useful in the manufacture of a medicament for treating obesityand/or diabetes.

[0303] The present invention also provides a process for preparing acompound of formula I:

[0304] or a pharmaceutically acceptable salts or stereoisomers thereof,wherein

[0305] —CLL′—(CH₂)_(n)—T is:

[0306] wherein R¹⁰ is a CBz or Boc protecting group, hydrogen,(C₁-C₈)alkyl, C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl, C₂-C₈ alkynyl, phenyl,aryl, or heteroaryl;

[0307] R² is:

[0308] Hydrogen, C₁-C₈ alkyl, CONHC₁-C₄ alkyl, (D)phenyl, oxo, or(D)C₃-C₇ cycloalkyl, provided that when R² is oxo, R² is on one of thering carbon atoms adjacent to Q bearing nitrogen atom;

[0309] R³ is: phenyl, aryl or thienyl; wherein phenyl, aryl and thienylare optionally substituted with one to three substituents independentlyselected from the group consisting of:

[0310] cyano, perfluoroalkoxy, halo, C₁-C₈ alkyl, (D)C₃-C₇ cycloalkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl;

[0311] R⁴ is hydrogen, C₁-C₈ alkyl, C₃-C₈ alkenyl, C(O)C₃-C₈ alkyl, or(D)phenyl;

[0312] Q is: —C(R^(a1))(R^(a2))(R^(a3))

[0313] Wherein R^(a1) is C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl,C₃-C₈ alkoxy, (D)C₃-C₇ cycloalkyl,.heterocyclic, alkylheterocyclic,(D)phenyl, aryl, 5 to 7 member benzofused bicyclic ring, or hetero6aryl,and wherein C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, (D)C₃-C₇cycloalkyl, heterocyclic, alkylheterocyclic, phenyl, aryl, 5- or7-membered benzofused bicyclic ring, and heteroaryl, are each optionallysubstituted with one to five substituents independently selected from R;

[0314] R is:

[0315] hydroxy,

[0316] halo,

[0317] C₁-C₈ alkyl,

[0318] C₂-C₈ alkenyl,

[0319] C₁-C₈ alkoxy,

[0320] C₁-C₄ haloalkyl,

[0321] (D)C₃-C₇ cycloalkyl,

[0322] (D)aryl,

[0323] (D)heteroaryl;

[0324] (D)C(O)C₁-C₄ alkyl,

[0325] (D)C(O)OC₁-C₄ alkyl,

[0326] (D)C(O)heteroaryl,

[0327] (CH₂)_(m)N(R⁸)₂,

[0328] (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl,

[0329] (CH₂)_(m)NR⁸SO₂ (C₁-C₄ alkyl),

[0330] (D)OC₁-C₄ alkyl,

[0331] (D)OC(O)C₁-C₄ alkyl,

[0332] (D)heterocyclic,

[0333] (D)SC₁-C₄ alkyl, or

[0334] (D)SO₂N(R⁸)₂;

[0335] wherein C₁-C₈ alkyl, C₁-C₈ alkoxy, C₃-C₇ cycloalkyl, phenyl,aryl, heterocyclic, and heteroaryl are optionally substituted with oneto five substituents independently selected from R⁸; and provided thatwhen R is halo or hydroxy it is not substituted on a carbon adjacent toa heteroatom;

[0336] R^(a2) is

[0337] C₁-C₈ alkyl,

[0338] C₂-C₈ alkenyl,

[0339] C2-C8 alkynyl,

[0340] (D)C₃-C₇ cycloalkyl,

[0341] phenyl,

[0342] aryl,

[0343] (CH₂)_(m)N(R⁸)₂,

[0344] (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl,

[0345] (CH₂)_(m)NR⁸C(O)OC₁-C₄ alkyl,

[0346] (CH₂)_(m)NR⁸SO₂(C₁-C₄ alkyl),

[0347] (CH₂)_(m)OC₁-C₄ alkyl,

[0348] (CH₂)_(m)OC(O)C₁-C₄ alkyl,

[0349] CON(R⁸)₂,

[0350] wherein for the group or subgroup —N(R⁸)₂, each R⁸ may combinewith the other to form a 5, 6, or 7-membered saturated or unsaturated,optionally substituted nitrogen containing heterocycle;

[0351] R^(a3) is selected from the group consisting of hydrogen, methyl,ethyl and propyl;

[0352] each R⁸ is independently:

[0353] hydrogen,

[0354] oxo,

[0355] C₁-C₈ alkyl,

[0356] C₂-C₈ alkenyl,

[0357] (D)C₃-C₇ cycloalkyl,

[0358] phenyl,

[0359] aryl or

[0360] heteroaryl,

[0361] wherein C₁-C₈ alkyl, C₁-C₈ alkenyl, C₃-C₇ cycloalkyl, phenyl,aryl and heteroaryl are optionally substituted with one to threesubstituents selected from the group consisting of C₁-C₈ alkyl, halo,and hydroxy; provided that the halo and hydroxy groups are notsubstituted on a carbon adjacent to a heteroatom;

[0362] R¹¹ is independently hydrogen, (C₁-C₈)alkyl, or (D)phenyl, oraryl;

[0363] D is a bond or C₁-C₄ alkyl;

[0364] y is 1 or 2;

[0365] m is 1-4;

[0366] n is 0-8; and

[0367] p is 0-4;

[0368] comprising the steps of:

[0369] a) reacting a compound having a structural formula 1:

[0370] with CH₂CH═C(O)OR^(a) wherein R^(a) is hydrogen or C₁-C₈ alkyland X is halo, in the presence of a catalyst and a base in a suitableorganic solvent to give the compound of formula 2

[0371] b) reductively aminating the compound of formula 2 in thepresence of amine to give a compound of formula 3

[0372] c) cyclizing the compound of formula 3 by Michael addition togive a compound of formula 4 or stereoisomers thereof

[0373] d) coupling the compound of formula 4 or stereoisomers thereofwherein R^(a) is H, with a compound of formula 5

[0374] wherein R^(a) is C₁-C₈ alkyl, to give a compound of formula 6

[0375] e) coupling the compound of formula 6 wherein R^(a) is H, with acompound having a structural formula

[0376] to afford the compound of formula 1.

[0377] The present invention also provides a process for preparing acompound of formula I:

[0378] wherein —LL′ (CH₂)_(n)—T is represented by the group:

[0379] R² is:

[0380] Hydrogen, C₁-C₈ alkyl, CONHC₁-C₄ alkyl, (D)phenyl, oxo, or(D)C₃-C₇ cycloalkyl, provided that when R² is oxo, R² is on one of thering carbon atoms adjacent to Q bearing nitrogen atom;

[0381] R³ is: phenyl, aryl or thienyl;

[0382] wherein phenyl, aryl and thienyl are optionally substituted withone to three substituents independently selected from the groupconsisting of:

[0383] cyano, perfluoroalkoxy, halo, C₁-C₈ alkyl, (D)C₃-C₇ cycloalkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl;

[0384] R⁴ is hydrogen, C₁-C₈ alkyl, C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl, or(D)phenyl;

[0385] Q is: —C(R^(a1))(R^(a2))(R^(a3))

[0386] Wherein R^(a1) is C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl,C₃-C₈ alkoxy, (D)C₃-C₇ cycloalkyl, heterocyclic, alkylheterocyclic,(D)phenyl, aryl, 5 to 7 member benzofused bicyclic ring, or heteroaryl,and wherein C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, (D)C₃-C₇cycloalkyl, heterocyclic, alkylheterocyclic, phenyl, aryl, 5- or7-membered benzofused bicyclic ring, and heteroaryl, are each optionallysubstituted with one to five substituents independently selected from R;

[0387] R is:

[0388] hydroxy,

[0389] halo,

[0390] C₁-C₈ alkyl,

[0391] C₂-C₈ alkenyl,

[0392] C₁-C₈ alkoxy,

[0393] C₁-C₄ haloalkyl,

[0394] (D)C₃-C₇ cycloalkyl,

[0395] (D)aryl,

[0396] (D)heteroaryl;

[0397] (D)C(O)C₁-C₄ alkyl,

[0398] (D)C(O)OC₁-C₄ alkyl,

[0399] (D)C(O)heteroaryl,

[0400] (CH₂)_(m)N(R⁸)₂,

[0401] (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl,

[0402] (CH₂)_(m)NR⁸SO₂(C₁-C₄ alkyl),

[0403] (D)OC₁-C₄ alkyl,

[0404] (D)OC(O)C₁-C₄ alkyl,

[0405] (D)heterocyclic,

[0406] (D)SC₁-C₄ alkyl, or

[0407] (D)SO₂N(R⁸)₂;

[0408] wherein C₁-C₈ alkyl, C₁-C₈ alkoxy, C₃-C₇ cycloalkyl, phenyl,aryl, heterocyclic, and heteroaryl are optionally substituted with oneto five substituents independently selected from R⁸; and provided thatwhen R is halo or hydroxy it is not substituted on a carbon adjacent toa heteroatom;

[0409] R^(a2) is

[0410] C₁-C₈ alkyl,

[0411] C₂-C₈ alkenyl,

[0412] C2-C8 alkynyl,

[0413] (D)C₃-C₇ cycloalkyl,

[0414] phenyl,

[0415] aryl,

[0416] (CH₂)_(m)N(R⁸)₂,

[0417] (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl,

[0418] (CH₂)_(m)NR⁸C(O)OC₁-C₄ alkyl,

[0419] (CH₂)_(m)NR⁸SO₂(C₁-C₄ alkyl),

[0420] (CH₂)_(m)OC₁-C₄ alkyl,

[0421] (CH₂)_(m)OC(O)C₁-C₄ alkyl,

[0422] CON(R⁸)₂,

[0423] wherein for the group or subgroup —N(R⁸)₂, each R⁸ may combinewith the other to form a 5, 6, or 7-membered saturated or unsaturated,optionally substituted nitrogen containing heterocycle;

[0424] R^(a3) is selected from the group consisting of hydrogen, methyl,ethyl and propyl;

[0425] each R⁸ is independently:

[0426] hydrogen,

[0427] oxo,

[0428] C₁-C₈ alkyl,

[0429] C₂-C₈ alkenyl,

[0430] (D)C₃-C₇ cycloalkyl,

[0431] phenyl,

[0432] aryl or

[0433] heteroaryl,

[0434] wherein C₁-C₈ alkyl, C₁-C₈ alkenyl, C₃-C₇ cycloalkyl, phenyl,aryl and heteroaryl are optionally substituted with one to threesubstituents selected from the group consisting of C₁-C₈ alkyl, halo,and hydroxy; provided that the halo and hydroxy groups are notsubstituted on a carbon adjacent to a heteroatom;

[0435] R¹⁰ is hydrogen, (C₁-C₈) alkyl, C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl,C₂-C₈ alkynyl, phenyl, aryl, or heteroaryl;

[0436] R¹¹ is independently hydrogen, (C₁-C₈)alkyl, or (D)phenyl, oraryl;

[0437] D is a bond or C₁-C₄ alkyl;

[0438] y is 1 or 2;

[0439] m is 1-4;

[0440] n is 0-8; and

[0441] p is 0-4;

[0442] comprising.the steps of:

[0443] a) esterifying a compound of formula 1 with an alcohol R^(a)OH

[0444] to form a compound of formula 2:

[0445] 2 wherein R^(a) is a group selected from C₁-C₄ alkyl, and (D)phenyl;

[0446] b) reacting a compound of formula 2 with R¹¹COR¹¹ to form acompound of formula

[0447] wherein R¹¹ is independently hydrogen, C₁-C₄ alkyl;

[0448] c) reacting a compound of formula 3 with an activating group toform a compound of formula 4

[0449] wherein A is an activating group;

[0450] d) deoxygenating the compound of formula 4 by hydrogenation toafford a compound of formula 5

[0451] e) optionally reacting the compound of formula 5 wherein HA is anacidic, with an inorganic base to form a compound of formula 6

[0452] wherein M is a univalent cation;

[0453] f) resolving the compound of formula 5 or the compound of formula6 wherein M is hydrogen to afford a chiral compound of formula 7

[0454] wherein Ra′ is H or R^(a);

[0455] g) coupling the compound of formula 7 with a compound of formula8

[0456] to afford a compound of formula 9:

[0457] h) coupling the compound of formula 9 with a compound of formula10:

[0458] to afford a compound of formula I:

[0459] Throughout the instant application, the following terms have theindicated meanings:

[0460] The term “C₁-C₈ alkyl” refers to a straight or branched saturatedhydrocarbon moiety containing from 1 to 8 carbon atoms. The term “C₁-C₄alkyl” refers specifically to methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl and t-butyl. A “C₁-C₈ haloalkyl” is a C₁-C₈alkyl moiety that is substituted with one or more halo atoms. Oneexample of a haloalkyl group is trifluoromethyl. A “C₁-C₈ alkoxy” groupor “C₁-C₈ alkoxy alkyl” group is a C₁-C₈ alkyl group attached through anoxygen linker.

[0461] The term “bezofused bicyclic” as used herein refers to a bicyclicring system.or radical wherein one of the rings is the benzene ring andwherein the point of attachment to the backbone of the compound theinvention is at other than the benzene ring. Unless otherwise specifiedit is to be understood that each ring of the benzofused bicyclcic isoptionally substituted with 1 to 3 substituents selected from alky,alkenyl, alkynyl, halo, haloalkyl, cyano, alkoxy, alkoxyalkyl, amino,substituted amino, thiol, formyl, carboxy alkyl, carboxyester,carbxamide, and sulfonamido groups.

[0462] The term “perfluoroalkoxy” as used herein refers to C₁-C₄ alkoxygroups having from 1 to 5 fluorine atoms, and includes for example,trifluoromethoxy, and pentafluoroethoxy.

[0463] The term “C₃-C₇ cycloalkyl” refers to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

[0464] The term “hydrocarbon diradical” refers to a straight or branchedchain of carbon atoms that may optionally be unsaturated at two or morecarbons. Thus, a hydrocarbon diradical according to the presentinvention includes alkylene, alkenylene and alkylidene moieties.Examples include but are not intended to be limited to methylene,ethylene, propylene, butylene, —CH(CH₃)CH(CH₃)—, —CH₂C(CH₃)₂—,—CH₂CH(CH₃)CH₂—, —CH═CHCH₂—, —CH═CH—, —CH₂C═CCH₂—, and the like.

[0465] The term “halo” refers to fluoro, chloro, bromo and iodo.

[0466] The term haloalkyl refers to a group having at least one carbonatom and as many halogen atoms as chemically sensible with or withouthydrogen atoms, and positional isomers thereof. The term haloalkyl,therefore, includes but is not limited to groups such astrifluoromethytl, methylchloride, dichloromethyl, pentylchloride, butylchloride, isopropyl chloride and the like.

[0467] As used herein a line “______” attached to a structure, partialstructure of a molecule or fragment thereof, without a group attached atthe end represents a point of attachment to another molecule, fragmentor radical unless otherwise indicated. For example, the group:

[0468] shows the piperazine groups as being attachable to anothermolecule or fragment at any position of the piperazine ring where thevalency allows i.e. the carbon atoms.

[0469] Unless otherwise specified, a “heterocycle” or “heterocyclic” or“heterocyclyl” group is a 5, 6 or 7 membered saturated, or partiallyunsaturated, or aromatic mono-cyclic or benzofused bicyclic ringcontaining 1-5 heteroatoms selected from N, S or O, wherein saidheterocycle is optionally substituted 1-4 times with: C₁-C₈ alkyl, C₁-C₄haloalkyl, (D)(C₃-C₇ cycloalkyl), unsubstituted-mono-cyclic nitrogencontaining heterocycle, (D)NR⁸R⁸, (D)NR⁸C(O)C₁-C₈ alkyl, (D)NR⁸SO₂(C₁-C₈alkyl), (D)SO(C₁-C₈ alkyl), (CH₂)_(m)SO₂R⁸, (CH₂)_(m)SO₂NR⁸R⁸ or(D)phenyl wherein:

[0470] R⁸ is as described herein; or when two R⁸ groups are attached tothe same nitrogen atom, said R⁸ groups, together with the nitrogen towhich they are attached, may combine to form a nitrogen containingheterocycle.

[0471] The variable “D” at each occurrence is independently a bond or aC₁-C₄ hydrocarbon diradical.

[0472] Unless otherwise specified, a “nitrogen containing heterocycle”is a heterocycle that contains 1-4 nitrogen atoms and optionallycontains 1 other heteroatom selected from O or S. Examples of nitrogencontaining heterocylces includes but is not limited to1,1-dioxo-1λ⁶-isothiazolidin-2-yl, pyrrole, thiazole, oxazolyl,imidazolyl, imidazolidinyl, 1,2,3-oxadiazolyl, piperidynyl,poiperazinyl, pyrazinyl, pyrimidinyl, 1,3,5-triazinyl, morpholinyl,thiomorpholinyl, pyridazinyl, 1,3-4 thiadiazolyl, isothiazolyl, eachoptionally substituted with 1 to 3 substituents including for examplehalo, oxo, carboxy esters, carboxyamides, C₁-C₈ alkyl.

[0473] The term “oxo” as used herein refers to an oxygen atom formed bythe combination of single bonds resulting in a double bond to oxygen.For example an “oxo” group formed by geminal substituents on a carbonatom depicts a carbonyl group ie., an oxo group bonded to carbon.

[0474] The term “composition”, as in pharmaceutical composition, isintended to encompass a product comprising the active ingredient(s), andthe inert ingredient(s) that make up the carrier. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

[0475] The term “pharmaceutical” when used herein as an adjective meanssubstantially non-deleterious to the recipient patient.

[0476] The term “unit dosage form” refers to physically discrete unitssuitable as unitary dosages for human subjects and other non-humananimals, each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical carrier.

[0477] The terms “treating” and “treat”, as used herein, include theirgenerally accepted meanings, i.e., preventing, prohibiting, restraining,alleviating, ameliorating, slowing, stopping, or reversing theprogression or severity of a pathological condition, or sequela thereof,described herein.

[0478] “Erectile dysfunction” is a disorder involving the failure of amale mammal to achieve erection, ejaculation, or both. Symptoms oferectile dysfunction include an inability to achieve or maintain anerection, ejaculatory failure, premature ejaculation, and inability toachieve an orgasm. An increase in erectile dysfunction is oftenassociated with age and is generally caused by a physical disease or asa side effect of drug treatment.

[0479] “Female sexual dysfunction” encompasses, without limitation,conditions such as a lack of sexual desire and related arousaldisorders, inhibited orgasm, lubrication difficulties, and vaginismus.

[0480] Because certain compounds of the invention contain an acidicmoiety (e.g., carboxy), the compound of formula I may exist as apharmaceutical base addition salt thereof. Such salts include thosederived from inorganic bases such as ammonium and alkali and alkalineearth metal hydroxides, carbonates, bicarbonates, and the like, as wellas salts derived from basic organic amines such as aliphatic andaromatic amines, aliphatic diamines, hydroxy alkamines, and the like.

[0481] Because certain compounds of the invention contain a basic moiety(e.g., amino), the compound of formula I can also exist as apharmaceutical acid addition salt. Such salts include sulfate,pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate,propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate,maleate, 2-butyne-1,4 dioate, 3-hexyne-2, 5-dioate, benzoate,chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, hippurate, beta-hydroxybutyrate, glycollate, maleate,tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and the like salts. Preferred acidaddition salts include the hydrochloride.

[0482] It will be understood that, as used herein, references to thecompounds of formula I or II are meant to also include thepharmaceutical salts.

[0483] Some of the compounds described herein may exist as tautomerssuch as keto-enol tautomers. The individual tautomers as well asmixtures thereof are encompassed within the scope of the presentinvention.

[0484] When describing various aspects of the present compounds, theterms “A domain”, “B domain” and “C domain” are used below. This domainconcept is illustrated below:

Utility

[0485] Compounds of formula I or II are effective as mnelanocortinreceptor agonists, particularly as agonists of the human MC-4 receptor.As melanocortin receptor agonists, the compounds of formula I or II areuseful in the treatment of diseases, disorders or conditions responsiveto the activation of one or more of the melanocortin receptorsincluding, but not limited to, MC-1, MC-2, MC-3, MC-4, or MC-5.Diseases, disorders or conditions receptive to treatment with a MC-4agonist include those mentioned supra and those described in WO00/74679, the teachings of which are herein incorporated by reference.

[0486] One embodiment of the invention, provides a novel process forpreparing compounds of formula I:

[0487] wherein —LL′ (CH₂)_(n)—T represents the group:

[0488] wherein R¹⁰ is a CBz or Boc protecting group, hydrogen,(C₁-C₈)alkyl, C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl, C₂-C₈ alkynyl, phenyl,aryl, or heteroaryl;

[0489] R² is:

[0490] Hydrogen, C₁-C₈ alkyl, CONHC₁-C₄ alkyl, (D)phenyl, oxo, or(D)C₃-C₇ cycloalkyl, provided that when R² is oxo, R² is on one of thering carbon atoms adjacent to Q bearing nitrogen atom;

[0491] R³ is: phenyl, aryl or thienyl;

[0492] wherein phenyl, aryl and thienyl are optionally substituted withone to three substituents independently selected from the groupconsisting of:

[0493] cyano, perfluoroalkoxy, halo, C₁-C₈ alkyl, (D)C₃-C₇ cycloalkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl;

[0494] R⁴ is hydrogen, C₁-C₈ alkyl, C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl, or(D)phenyl;

[0495] Q is: —C(R^(a1)) (R^(a2)) (R^(a3))

[0496] Wherein R^(a1) is C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl,C₃-C₈ alkoxy, (D)C₃-C₇ cycloalkyl, heterocyclic, alkylheterocyclic,(D)phenyl, aryl, 5 to 7 member benzofused bicyclic ring, or heteroaryl,and wherein C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, (D)C₃-C₇cycloalkyl, heterocyclic, alkylheterocyclic, phenyl, aryl, 5- or7-membered benzofused bicyclic ring, and heteroaryl, are each optionallysubstituted with one to five substituents independently selected from R;

[0497] R is:

[0498] hydroxy,

[0499] halo,

[0500] C₁-C₈ alkyl,

[0501] C₂-C₈ alkenyl,

[0502] C₁-C₈ alkoxy,

[0503] C₁-C₄ haloalkyl,

[0504] (D)C₃-C₇ cycloalkyl,

[0505] (D)aryl,

[0506] (D)heteroaryl;

[0507] (D)C(O)C₁-C₄ alkyl,

[0508] (D)C(O)OC₁-C₄ alkyl,

[0509] (D)C(O)heteroaryl,

[0510] (CH₂)_(m)N(R⁸)₂,

[0511] (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl,

[0512] (CH₂)_(m)N⁸SO₂(C₁-C₄ alkyl),

[0513] (D)OC₁-C₄ alkyl,

[0514] (D)OC(O)C₁-C₄ alkyl,

[0515] (D)heterocyclic,

[0516] (D)SC₁-C₄ alkyl, or

[0517] (D)SO₂N(R⁸)₂;

[0518] wherein C₁-C₈ alkyl, C₁-C₈ alkoxy, C₃-C₇ cycloalkyl, phenyl,aryl, heterocyclic, and heteroaryl are optionally substituted with oneto five substituents independently selected from R⁸; and provided thatwhen R is halo or hydroxy it is not substituted on a carbon adjacent toa heteroatom;

[0519] R^(a2) is

[0520] C₁-C₈ alkyl,

[0521] C₂-C₈ alkenyl,

[0522] C2-C8 alkynyl,

[0523] (D)C₃-C₇ cycloalkyl,

[0524] phenyl,

[0525] aryl,

[0526] (CH₂)_(m)N(R⁸)₂,

[0527] (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl,

[0528] (CH₂)_(m)NR⁸C(O)OC₁-C₄ alkyl,

[0529] (CH₂)_(m)NR⁸SO₂(C₁-C₄ alkyl),

[0530] (CH₂)_(m)OC₁-C₄ alkyl,

[0531] (CH₂)_(m)OC(O)C₁-C₄ alkyl,

[0532] CON(R⁸)₂,

[0533] wherein for the group or subgroup —N(R⁸)₂, each R⁸ may combinewith the other to form a 5, 6, or 7-membered saturated or unsaturated,optionally substituted nitrogen containing heterocycle;

[0534] R^(a3) is selected from the group consisting of hydrogen, methyl,ethyl and propyl;

[0535] each R⁸ is, independently:

[0536] hydrogen,

[0537] oxo,

[0538] C₁-C₈ alkyl,

[0539] C₂-C₈ alkenyl,

[0540] (D)C₃-C₇ cycloalkyl,

[0541] phenyl,

[0542] aryl or

[0543] heteroaryl,

[0544] wherein C₁-C₈ alkyl, C₁-C₈ alkenyl, C₃-C₇ cycloalkyl, phenyl,aryl and heteroaryl are optionally substituted with one to threesubstituents selected from the group consisting of C₁-C₈ alkyl, halo,and hydroxy; provided that the halo and hydroxy groups are notsubstituted on a carbon adjacent to a heteroatom;

[0545] R¹¹ is independently hydrogen, (C₁-C₈)alkyl, or (D)phenyl, oraryl;

[0546] D is a bond or C₁-C₄ alkyl;

[0547] y is 1 or 2;

[0548] m is 1-4;

[0549] n is 0-8; and

[0550] p is 0-4; and comprising the steps of:

[0551] a) reacting a compound formula 1:

[0552]  wherein X is halo and R¹¹ is independently, hydrogen or C₁-C₄alkyl, with CNCH₂CO₂R^(a) wherein R^(a) is C₁-C₈ alkyl, or benzyl toafford a compound of formula 2:

[0553] b) protecting the compound of formula 2 to form the compound offormula 3:

[0554] c) hydrogenating the compound of formula 3 to afford a compoundof formula 4:

[0555]  wherein R^(a′) is H or R^(a);

[0556] d) coupling the compound of formula 4 wherein R^(a′) is hydrogenwith a compound of formula 5:

[0557]  to afford a compound of formula 6:

[0558] e) coupling the compound of formula 6 with a compound of formrula7:

[0559]  to afford a compound of formula I:

Preferred Compounds of the Invention

[0560] The following listing sets out several groups of preferredcompounds organized by domains. It will be understood that each of thelistings may be combined with other listings to create additional groupsof preferred compounds.

[0561] A Domains

[0562] Q is: —C(R^(a1))(R^(a2))(R^(a3))

[0563] Wherein R^(a1) is C₁-C₈ alkyl, C₁-C₈ alkenyl, cycloalkyl,heterocyclic, phenyl, aryl, or heteroaryl, and wherein C₁-C₈ alkyl,C₁-C₈ alkenyl, cycloalkyl, heterocyclic, phenyl, aryl, or heteroaryl areeach optionally substituted with one to five substituents independentlyselected from R, wherein R has been described supra.

[0564] a) Q is: —C(R^(a1)) (R^(a2)) (R^(a3))

[0565] Wherein R^(a1) is phenyl, benzyl, cyclohexane, cyclopentane orcycloheptane each optionally substituted with one to three substituents(R) selected from the group consisting of C₁-C₈ alkyl, halo, andhaloalkyl;

[0566] b) Wherein R^(a2) is

[0567] C₁-C₈ alkyl,

[0568] C₁-C₈ alkenyl,

[0569] (D)C₃-C₇ cycloalkyl,

[0570] (D)N(R⁸)₂,

[0571] (D)NR⁸C(O)C₁-C₄ alkyl,

[0572] (D)NR⁸COOR⁸,

[0573] (D)NR⁸SO₂(C₁-C₄ alkyl),

[0574] (D)CON(R⁸)₂,

[0575] wherein for the group or subgroup —N(R⁸)₂, each R⁸ may combinewith the other to form a nitrogen containing heterocycle;

[0576] c) R^(a3) is selected from the group consisting of hydrogen,methyl ethyl and propyl.

[0577] d) R^(a3) is hydrogen.

[0578] e) For the compounds of formula II, the Z ring is a saturatedring or Z is phenyl.

[0579] f) the A domain is selected from those exemplified below in thePreparations and Examples sections; p1 g) R² is hydrogen, C₁-C₈ alkyl,(D)phenyl, CONHC₁-C₄ alkyl, oxo, or (D)C₃-C₇ cycloalkyl;

[0580] B Domains

[0581] h) R³ is phenyl optionally para-substituted with halo,trifluoromethyl, benzyl, benzyloxy, C₁-C₂ alkyl or C₁-C₂ alkoxy;

[0582] i) R³ is phenyl para-substituted with chloro;

[0583] j) the B domain is a diradical with the C-terminus attaching tothe A-domain and the N-terminus attaching to the C domain and isselected from the group consisting of:

[0584] k) the B domain is a diradical with the C-terminus attaching tothe A-domain and the N-terminus attaching to the C domain and isselected from the group consisting of:

[0585] C Domains

[0586] The C-domain is represented by the formula —CLL¹—(CH₂)_(n)—T or—CLL¹—(CH₂)_(n)—T′. Preferred embodiments of the C-domain or aspectsthereof include:

[0587] 1) the C domain wherein T or T′ is a moiety of the formula:

[0588] wherein R, R¹⁰, R¹¹, R¹² and R¹³ are as described previously;

[0589] m) T or T′ for the C domain is a moiety of the formula:

[0590] n) the C domain is a moiety selected from the group consistingof:

[0591] Most preferred R⁴ groups include hydrogen, and C₁-C₈ alkyl.

[0592] For the “C” domain it is preferred that both L and L′ arehydrogen or combine to form an oxo group.

[0593] Salt Forms

[0594] o) the compound of formula I is an acid addition salt;

[0595] p) the compound of formula I is the hydrochloride salt.

[0596] A preferred compound of the invention is a compound selected fromthe group consisting of those in Table A below: TABLE A Add

nal Structure Info NAME

“A” isomer #2 Isoquinoline-3-carboxylic acid (1-(4-chloro-benzyl)-2-{4-[2- diethylamino-1-(2-fluoro-phenyl)- ethyl]-piperazin-1-yl}- 2-oxo-ethyl)-amide

“isomer #2 for “A” and “C” 1,1-Dimethyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (1- (4-chloro-benzyl)-2-{4-[2-diethylamino-1-(2-fluoro-phenyl)- ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide

“A” isomer #2 N-(1-(4-Chloro-benzyl)-2-{4-[1-(2-chloro-phenyl)-2-diethylemino- ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2-methyl-2,3-dihydro-1H- isoindol-1-yl)-acetamide

“A” isomer #2 N-(1-(4-Chloro-benzyl)-2-{4-[2-diethylamino-1-(2-fluoro-phenyl)- ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2-methyl-2,3-dihydro-1H- isoindol-1-yl)-acetamide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid (1-(4-chloro-benzyl)-2-{4-[1-(2-chloro-phenyl)- 2-dimethylamino-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid (1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1-(2- trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide

isomer #1 (of 2 - HPLC 1,2,3,4-Tetrahydro-isoquinoline-3- carboxylicacid (1-(4-chloro- benzyl)-2-{4-[2-diethylamino-1-(2-trifluoromethyl-phenyl)-ethyl]- piperazin-1-yl}-2-oxo-ethyl)-amide

isomer #2 (of 2 - HPLC) 1,2,3,4-Tetrahydro-isoquinoline-3- carboxylicacid (1-(4-chloro- benzyl)-2-{4-[2-diethylamino-1-(2-trifluoromethyl-phenyl)-ethyl]- piperazin-1-yl}-2-oxo-ethyl)-amide

isomer #2-UNK (of 4 - HPLC) N-(1-(4-Chloro-benzyl)-2-{4-[2-diethylamino-1-(2-trifluoromethyl- phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H- isoindol-1-yl)-acetamide

isomer #4-UNK (of 4 - HPLC) N-(1-(4-Chloro-benzyl)-2-{4-[2-diethylamino-1-(2-trifluoromethyl- phenyl)-ethyl]-piperazin-1-yl}-2-isoindol-1-yl)-acetamide

isomer #2 (of 4 - HPLC) N-{1-[4-(2-Diethylamino-1-phenyl-ethyl)-piperazine-1-carbonyl]-3- methylene-hex-4-enyl}-2-(4-methyl-3-vinyl-1,2,5,6-tetrahydro- pyridin-2-yl)-acetamide

isomer #1 (of 2 - HPLC) N-(1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1-(2-trifluoromethyl- phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H- isoindol-1-yl)-acetamide

isomer #2 (of 2 - HPLC) N-(1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1-(2-trifluoromethyl- phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H- isoindol-1-yl)-acetamide

isomer #1 (of 2 - HPLC) N-(1-(4-Chloro-benzyl)-2-{4-[2-diethylamino-1-(2-trifluoromethyl- phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H- isoindol-1-yl)-acetamide

isomer #2 (of 2 - HPLC) N-(1-(4-Chloro-benzyl)-2-{4-[2-diethylamino-1-(2-trifluoromethyl- phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H- isoindol-1-yl)-acetamide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid (1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1-(2- fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid (1-(4-chloro-benzyl)-2-(4-[1-(2-fluoro-phenyl)- 2-methanesulfonylamino-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide

N-(1-(4-chioro-beazyl)-2-{4-[2- diethylamino-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo- ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-(1-(4-chloro-benzyl)-2-{4-[2- diethylamino-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo- ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-(1-(4-Chloro-benzyl)-2-{4-[2- (ethyl-methanesulfonyl-amino)-1-(2-fluoro-phenyl)-ethyl]- piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)- acetamide

3-(4-Chloro-phenyl)-1-{4-[2- diethylamino-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2- [(1,2,3,4-tetrahydro-isoquinolin-3-ylmethyl)-amino]-propan-1-one

N-[2-(4-{3-(4-Chloro-phenyl)-2- [(1,2,3,4-tetrahydro-isoquinolin-3-ylmethyl)-amino]-propionyl}- phenyl)-ethyl]-methanesulfonamide

N-[2-(4-{3-(4-Chloro-phenyl)-2- [(1,2,3,4-tetrahydro-isoquinolin-3-ylmethyl)-amino]-propionyl}- piperazin-1-yl)-2-(2-fluoro-phenyl)-ethyl]-N-ethyl- methanesulfonamide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid (1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1- (2,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid (1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1- (2,6-difluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid (1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1-(2- fluoro-4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-2-oxo- ethyl)-amide

“A” isomer #2 N-(1-(4-Chloro-benzyl)-2-{4-[2-diethylamino-1-(2-fluoro-phenyl)- ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol- 1-yl)-acetamide

“A” isomer #2 1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid(1-(4-chloro- benzyl)-2-{4-[2-diethylamino-1-(2-fluoro-phenyl)-ethyl]-piperazin-1- yl}-2-oxo-ethyl)-amide

“A” isomer #2 1,2,3,4-Tetrahydro-isoquinline-3- carboxylic acid(1-(4-chloro- benzyl)-2-{4-[1-(2-chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1- yl}-2-oxo-ethyl)-amide

“A” isomer #2 1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid(1-(4-chloro- benzyl)-2-{4-[1-(2-chloro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo- ethyl)-amide

[2-(4-{3-(4-Chloro-phenyl)-2- [(1,2,3,4-tetrahydro-isoquinoline-3-carbonyl)-amino]-propionyl}- piperazin-1-yl)-2-(2,4-difluoro-phenyl)-ethyl]-carbamic acid methyl ester

“A” isomer #2 N-(1-(4-Chloro-benzyl)-2-{4-[1-(2-chloro-phenyl)-2-diethylamino- ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol- 1-yl)-acetamide

“A” isomer #2 N-(1-(4-Chloro-benzyl)-2-{4-[1-(2-chloro-phenyl)-2-diethylamino- ethyl]-piperazine-1-yl}-2-oxo-ethyl)-2-(1,2,3,4-tetrahydro- isoquinolin-1-yl)-acetamide

“A” isomer #2 N-(1-(4-Chloro-benzyl)-2-{4-[1-(2-chloro-phenyl)-2-diethylamino- ethyl]-piperazine-1-yl}-2-oxo-ethyl)-2-(1,2,3,4-tetrahydro- isoquinolin-1-yl)-acetamide

“A”isomer #2, “C” isomer #1 N-(1-(4-Chloro-benzyl)-2-{4-[2-diethylamino-1-(2-fluoro-phenyl)- ethyl]piperazin-1-yl}-2-oxo-ethyl)-2-(1,2,3,4-tetrahydro- isoquinolin-1-yl)-acetamide

“A”isomer #2, “C” isomer #1 N-(1-(4-Chloro-benzyl)-2-{4-[2-diethylamino-1-(2-fluoro-phenyl)- ethyl]piperazin-1-yl}-2-oxo-ethyl)-2-(1,2,3,4-tetrahydro- isoquinolin-1-yl)-acetamide

[2-(4-{3-(4-Chloro-phenyl)-2- [(1,2,3,4-tetrahydro-isoquinoline-3-carbonyl)-amino]-propionyl}- piperazin-1-yl)-2-(2-fluoro-phenyl)-ethyl]-carbamic acid methyl ester

[2-(4-{3-(4-Chloro-phenyl)-2- [(1,2,3,4-tetrahydro-isoquinoline-3-carbonyl)-amino]-propionyl}- piperazin-1-yl)-2-(2-fluoro-phenyl)-ethyl]-carbamic acid ethyl ester

[2-(4-{3-(4-Chloro-phenyl)-2- [(1,2,3,4-tetrahydro-isoquinoline-3-carbonyl)-amino]-propionyl}- piperazin-1-yl)-2-(2-fluoro-phenyl)-ethyl]-carbamic acid isopropyl ester

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid [2-{4-[2-(acetyl-methyl-amino)-1-(2-fluoro-phenyl)- ethyl]-piperazin-1-(4-chloro-benzyl)-2-oxo-ethyl]-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid {1-(4-chloro-benzyl)-2-[4-(2-dipropylamino-1- phenyl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid {1-(4-chloro-benzyl)-2-[4-(2-dipropylamino-1- phenyl-ethyl-piperazin-1-yl]-2-oxo-ethyl}-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid (1-(4-chloro-benzyl)-2-oxo-2-[4-(1-phenyl-2- yl]-ethyl}-amide

7-Fluoro-1,2,3,4-tetrahydro- isoquinoline-3-carboxylic acid {1-(4-chloro-benzyl)-2-[4-(2- diethylamino-1-phenyl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

“C” isomer #1 3-Methyl-1,2,3,4-tetrahydro- isoquinoline-3-carboxylicacid (1- (4-chloro-benzyl)-2-{4-[1-(4- chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1-yl}-2-oxo- ethyl)-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid [2-{4-[2-(acetyl-ethyl-amino)-1-(2-fluoro-phenyl)- ethyl]piperazin-1-yl}-1-(4-chloro-benzyl)-2-oxo-ethyl]-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid (1-(4-chloro-benzyl)-2-{4-[2-(ethyl-propionyl- amino)-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl }-2-oxo-ethyl)-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid (1-(4-chloro-benzyl)-2-{4-[2-(ethyl-isobutyryl-amino)-1-(2-fluoro-phenyl)-ethyl]piperazin-1-yl }-2-oxo-ethyl)-amide

[2-(4-{3-(4-Chloro-phenyl)-2- [(1,2,3,4-tetrahydro-isoquinoline-3-carbonyl)-amino]-propionyl}- piperazin-1-yl)-2-(2-fluoro-phenyl)-ethyl}-ethyl-carbamic acid methyl ester

[2-(4-{3-(4-Chloro-phenyl)-2- [(1,2,3,4-tetrahydro-isoquinoline-3-carbonyl)-amino]-propionyl}- piperazin-1-yl)-2-(2-fluoro-phenyl)-ethyl}-ethyl-carbamic acid ethyl ester

[2-(4-{3-(4-Chloro-phenyl)-2- [(1,2,3,4-tetrahydro-isoquinoline-3-carbonyl)-amino]-propionyl}- piperazin-1-yl)-2-(2-fluoro-phenyl)-ethyl}-ethyl-carbamic acid isopropyl ester

N-[2-{4-[2-[Acetyl-(2-ethyl- butyl)-amino]-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-yl}-1-(4- chloro-benzyl)-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)- acetamide

N-[2-{4-[2-(Acetyl- cyclohexylmethyl-amino)-1-(2-fluoro-phenyl)-ethyl]-piperazin-1- yl}-1-(4-chloro-benzyl)-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol- 1-yl)-acetamide

“A” isomer #2 N-(1-(4-Chloro-benzyl)-2-{4-[1-(2-chloro-phenyl)-2-(ethyl- methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2- (2,3-dihydro-1H-isoindol-1-yl)-acetamide

“A” isomer #2 N-(1-(4-Chloro-benzyl)-2-{4-[1-(2-chloro-phenyl)-2-(ethyl- methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2- (1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamide

“A” isomer #2 N-(1-(4-Chloro-benzyl)-2-{4-[2-diethylamino-1-(2-trifluoromethyl- phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethy)-2-(1,2,3,4-tetrahydro- isoquinolin-1-yl)-acetamide

“A” isomer #2 N-(1-(4-Chloro-benzyl)-2-{4-[1-(2- fluoro-phenyl)-2-methanesulfonylamino-ethyl]- piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)- acetamide

3-(4-Chloro-phenyl)-1-[4-(2- diethylamino-1-phenyl-ethyl)-piperazin-1-yl }-2-[(1,2,3,4- tetrahydro-isoquinolin-3-ylmethyl)-amino]-propan-1-one

“A”isomer #2, “C” isomer #1 N-(1-(4-Chloro-benzyl)-2-{4-[2-diethylamino-1-(2-fluoro-phenyl)- ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(1-methyl-2,3-dihydro-1H- isoindol-1-yl)-acetamide

“A”isomer #2, “C” isomer #1 N-(1-(4-Chloro-benzyl)-2-{4-[2-diethylamino-1-(2-fluoro-phenyl)- ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(1-methyl-2,3-dihydro-1H- isoindol-1-yl)-acetamide

“A” isomer #2 1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid(1-(4-chloro- benzyl)-2-{4-[2-diethylamino-1-(2-trifluoromethyl-phenyl)-ethyl]- piperazin-1-yl}-2-oxo-ethyl)-amide

“A” isomer #2 1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid(1-(4-chloro- benzyl)-2-{4-[2-diethylamino-1-(2-trifluoromethyl-phenyl)-ethyl]- piperazin-1-yl}-2-oxo-ethyl)-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid (1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1-(4- trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide

N-(1-(4-Chloro-benzyl)-2-{4-[1-(4- chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1-yl}-2-oxo- ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

1,2,3,4,4a,8a,-Hexahydro- isoquinoline-3-carboxylic acid [2-[4-(2-diethylamino-1-p-tolyl- ethyl)-piperazin-1-yl]-1-(4-methyl-benzyl)-2-oxo-ethyl]-amide

N-[2-[4-(2-Diethylamino-1-p-tolyl- ethyl)-piperazin-1-yl]-1-(4-methyl-benzyl)-2-oxo-ethyl]-2- (2,3-dihydro-1H-isoindol-1-yl)- acetamide

“A” isomer #1 N-[2-{4-[1-(2-Chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1- yl}-1-(4-methyl-benzyl)-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol- 1-yl)-acetamide

“A” isomer #2 N-[2-{4-[1-(2-Chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1- yl}-1-(4-methyl-benzyl)-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol- 1-yl)-acetamide

“A” isomer #1 N-[2-{4-[1-(2-Chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1- yl}-1-(4-methyl-benzyl)-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol- 1-yl)-acetamide

“A” isomer #2 N-[2-{4-[1-(2-Chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1- yl}-1-(4-methyl-benzyl)-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol- 1-yl)-acetamide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid [2-{4-[2-diethylamino-1-(2-methoxy-phenyl)- ethyl]-piperazin-1-yl}-1-(4-methyl-benzyl)-2-oxo-ethyl]-amide

N-[2-{4-[2-Diethylamino-1-(2- methoxy-phenyl)-ethyl]-piperazin-1-yl}-1-(4-methyl-benzyl)-2-oxo- ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

“C” ]isomer #1 N-[2-{4-[1-(2-Chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1- yl}-1-(4-methyl-benzyl)-2-oxo-ethyl]-2-(1-methyl-2,3-dihydro-1H- isoindol-1-yl)-acetamide

“C” ]isomer #2 N-[2-{4-[1-(2-Chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1- yl}-1-(4-methyl-benzyl)-2-oxo-ethyl]-2-(1-methyl-2,3-dihydro-1H- isoindol-1-yl)-acetamide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid [2-{4-[1-(2-chloro-phenyl)-2- methanesulfonylamino-ethyl]-benzyl)-2-oxo-ethyl]-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid [2-{4-[1-(2-chloro-phenyl)-2-diethylamino- ethyl]-piperazin-1-yl}-1-(4-methyl-benzyl)-2-oxo-ethyl]-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid {1-(4-chloro-benzyl)-2-[4-(diethylamino-1- phenyl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

“A” isomer #2 1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid(1-(4-chloro- benzyl)-2-{4-[2-(ethyl- methanesulfonyl-amino)-1-(2-fluoro-phenyl)-ethyl]-piperazin-1- yl}-2-oxo-ethyl)-amide

“A” isomer #1 1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid(1-(4-chloro- benzyl)-2-{4-[1-(4-chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1- yl}-2-oxo-ethyl)-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid {1-(4-chloro-benzyl)-2-[4-(2-diethylamino-1-o-tolyl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

“A”isomer #2, “C” isomer #2 N-(1-(4-Chloro-benzy)-2-{4-[1-(2-chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid {1-(4-chloro-benzyl)-2-[4-(2-diethylamino-1- phenyl-ethyl)-[1,4]diazepan-1-yl]-2-oxo-ethyl}-amide

N-{1-(4-Chloro-benzyl)-2-[4-(2- diethylamino-1-phenyl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2- (2,3-dihydro-1H-isoindol-1-yl)-acetamide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid {1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2- diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid {1-(4-chloro-benzyl)-2-[4-(1-cyclopentyl-2- diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid {1-(4-chloro-benzyl)-2-[4-(1-cycloheptyl-2- diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid {1-(4-chloro-benzyl)-2-[4-(1-cyclohexylmethyl- 2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid (1-(4-chloro-benzyl)-2-{4-[1-cyclohexyl-2- (ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo- ethyl)-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid (1-(4-chloro-benzyl)-2-{4-[1-cyclopentyl-2- (ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo- ethyl)-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid (1-(4-chloro-benzyl)-2-{4-[1-cyclohexylmethyl- 2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo- ethyl)-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid {1-(4-chloro-benzyl)-2-[4-[1-cyclohexyl-2- methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid {1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2- pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid [2-{4-[2-(benzyl-methanesulfonyl-amino)-1- cyclohexyl-ethyl]-piperazin-1-yl}-1-(4-chloro-benzyl)-2-oxo-ethyl]- amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid [2-[4-[(2-acetylamino-1-cyclohexyl-ethyl)- piperazin-1-yl]-1-(4-chloro-benzyl)-2-oxo-ethyl]-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid {1-(4-chloro-benzyl)-2-[4-[1-cyclohexylmethyl- 2-methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid {1-(4-chloro-benzyl)-2-[4-[1-cyclohexylmethyl- 2-morpholin-4-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid {1-(4-chloro-benzyl)-2-[4-[1-cyclohexylmethyl- 2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid {1-(4-chloro-benzyl)-2-[4-[1-cyclohexylmethyl- 2-piperidin-1-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

N-{1-(4-chloro-benzyl)-2-[4-(1- cycohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2- (2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2- (2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2- (2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-{1-(4-chloro-benzyl)-2-{4-[1- cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]- piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)- acetamide

N-{1-(4-chloro-benzyl)-2-{4-[1- cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]- piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)- acetamide

N-{1-(4-chloro-benzyl)-2-{4-[1- cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]- piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)- acetamide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexyl-2-methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo- ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexyl-2-methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo- ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexyl-2-methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo- ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-[2-{4-(Acethyl-ethyl-amino)-1- cyclohexyl-ethyl]-piperazin-1-yl}-1-(4-chloro-benzyl)-2-oxo-ethyl]- 2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-[2-{4-(Acethyl-ethyl-amino)-1- cyclohexyl-ethyl]-piperazin-1-yl}-1-(4-chloro-benzyl)-2-oxo-ethyl]- 2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-[2-{4-(Acethyl-ethyl-amino)-1- cyclohexyl-ethyl]-piperazin-1-yl}-1-(4-chloro-benzyl)-2-oxo-ethyl]- 2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-(1-(4-chloro-benzyl)2-{4-[1- cyclohexyl-2-(2,5-dioxo-pyrrolidin-yl)-ethyl]-piperazin-1- yl}-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-(1-(4-chloro-benzyl)2-{4-[1- cyclohexyl-2-(2,5-dioxo-pyrrolidin-yl)-ethyl]-piperazin-1- yl}-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-(1-(4-chloro-benzyl)2-{4-[1- cyclohexyl-2-(2,5-dioxo-pyrrolidin-yl)-ethyl]-piperazin-1- yl}-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-(1-(4-chloro-benzyl)2-{4-[1- cyclohexyl-2-(2-oxo-pyrrolidin-yl)-ethyl]-piperazin-1-yl}-2-oxo- ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-(1-(4-chloro-benzyl)2-{4-[1- cyclohexyl-2-(2-oxo-pyrrolidin-yl)-ethyl]-piperazin-1-yl}-2-oxo- ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-actamide

2-{4-[3-(4-Chloro-benzyl)2-(2-2,3- dihydro-1H-isoindol-1-yl-acetylamino)-propionyl]-piperazin- 1-yl}-3-cyclohexyl-N,N-diethyl-propionamide

2-{4-[3-(4-Chloro-benzyl)2-(2-2,3- dihydro-1H-isoindol-1-yl-acetylamino)-propionyl]-piperazin- 1-yl}-3-cyclohexyl-N,N-diethyl-propionamide

2-{4-[3-(4-Chloro-benzyl)2-(2-2,3- dihydro-1H-isoindol-1-yl-acetylamino)-propionyl]-piperazin- 1-yl}-3-cyclohexyl-N,N-diethyl-propionamide

N-(1-(4-chloro-benzyl)2-[4-(1- cyclohexyl-2-oxo-2-pyrrolidin-yl-ethyl)-piperazin-1-yl]-2-oxo- ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexylmethyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo- ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexylmethyl-2-morpholine-4-yl-ethyl)-piperazin-1-yl]-2-oxo- ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexylmethyl-2-piperidin-1-yl-ethyl)-piperazin-1-yl]-2-oxo- ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexylmethyl-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-2-oxo- ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-{1-(4-chloro-benzyl)-2-{4-[1- cyclohexylmethyl-2-(ethyl-methanesulfonyl-amino)-ethyl]- piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)- acetamide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexylmethyl-2-methanesulfonylamino-ethyl)- piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)- acetamide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2- (1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2- (1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2- methyl-2,3-dihydro-1H-isoindol-1-yl)-acetamide

1,1,-Dimethyl-1,2,3,4-tetrahydro- isoquinoline-3-carboxylic acid {1-(4-chloro-benzyl)-2-[4-(1- cyclohexyl-2-diethlamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

1,1,-Dimethyl-1,2,3,4-tetrahydro- isoquinoline-3-carboxylic acid {1-(4-chloro-benzyl)-2-[4-(1- cyclohexyl-2-diethlamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide

Isoquinoline-3-carboxylic acid {1- (4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-diethylamino-ethyl)- piperazin-1-yl]-2-oxo-ethyl}-amide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]- piperazin-1-yl]-2-oxo-ethyl}-2-(1,2,3,4-tetrahydro-isoquinolin-1- yl)-acetamide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]- piperazin-1-yl]-2-oxo-ethyl}-2-(1,2,3,4-tetrahydro-isoquinolin-1- yl)-acetamide

N-{1-(4-chloro-benzyl)-2-{4-[1- cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]- piperazin-1-yl}-2-oxo-ethyl)-2-(2-methyl-2,3-dihydro-1H-isoindol-1- yl)-acetamide

Isoquinoline-3-carboxylic acid {1- (4-chloro-benzyl)-2-{4-[1-cyclohexyl-2-(ethyl- methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl}-amide

1,1-Dimethyl-1,2,3,4-Tetrahydro- isoquinoline-3-carboxylic acid (1-(4-chloro-benzyl)-2-{4-[1- cyclohexylmethyl-2-(ethyl-methanesulfonyl-amino)-ethyl]- piperazin-1-yl}-2-oxo-ethyl)-amide

1,1-Dimethyl-1,2,3,4-Tetrahydro- isoquinoline-3-carboxylic acid (1-(4-chloro-benzyl)-2-{4-[1- cyclohexylmethyl-2-(ethyl-methanesulfonyl-amino)-ethyl]- piperazin-1-yl}-2-oxo-ethyl)-amide

1,1-Dimethyl-1,2,3,4-Tetrahydro- isoquinoline-3-carboxylic acid (1-(4-chloro-benzyl)-2-{4-[1- cyclohexylmethyl-2-(ethyl-methanesulfonyl-amino)-ethyl]- piperazin-1-yl}-2-oxo-ethyl)-amide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexyl-2-methanesulfonyl-amino-ethyl]-piperazin-1-yl]-2- oxo-ethyl}-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexyl-2-methanesulfonyl-amino-ethyl]-piperazin-1-yl]-2- oxo-ethyl}-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexyl-2-methanesulfonyl-amino-ethyl]-piperazin-1-yl]-2- oxo-ethyl}-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamide

N-{1-(4-chloro-benzyl)-2-[4-(1- cyclohexyl-2-methanesulfonyl-amino-ethyl]-piperazin-1-yl]-2- oxo-ethyl}-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamide

N-{1-(4-chloro-benzyl)-2-{4-[1- cyclohexyl-2-methanesulfonyl-amino-ethyl]-piperazin-1-yl}-2- oxo-ethyl)-2-(2-methyl-2,3-dihydro-1H-isoindol-1-yl)- acetamide

1,1-Dimethyl-1,2,3,4-tetrahydro- isoquinoline-3-carboxylic acid {1-(4-chloro-benzyl)-2-[4-[1- cyclohexyl-2-methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo- ethyl}-amide

1,1-Dimethyl-1,2,3,4-tetrahydro- isoquinoline-3-carboxylic acid {1-(4-chloro-benzyl)-2-[4-[1- cyclohexyl-2-methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo- ethyl}-amide

1,1-Dimethyl-1,2,3,4-tetrahydro- isoquinoline-3-carboxylic acid {1-(4-chloro-benzyl)-2-[4-[1- cyclohexyl-2-methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo- ethyl}-amide

1,2,3,4-Tetrahydro-isoquinoline-3- carboxylic acid [2-[4-(1-benzyl-2-diethylamino-ethyl)-piperazin-1- yl]-1-(4-chloro-benzyl)-2-oxo-ethyl]-amide

N-{1-(4-Chloro-benzyl)-2-[4-(1- cyclohexy-3-methyl-butyl)-piperazin-1-yl]-2-oxo-ethyl}-2- (2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-{1-(4-Chloro-benzyl)-2-[4-(2- cyclohexyl-1-cyclohexylmethyl-ethyl)-piperazin-1-yl]-2-oxo- ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide

N-(1-(4-Chloro-benzyl)-2-{4-[1- cyclohexyl-2-(isobutyl-methanesulfonyl-amino)-ethyl]- piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)- acetamide

N-(1-(4-Chloro-benzyl)-2-{4-[1- cyclohexyl-2-(isobutyl-methanesulfonyl-amino)ethyl]- piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)- acetamide

N-[2-{4-[2-(Acetyl-isobutyl- amino)-1-cyclohexyl-ethyl]-piperazin-1-yl}-1-(4-chloro- benzyl)-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)- acetamide

N-[2-{4-[2-(Acetyl-isobutyl- amino)-1-cyclohexyl-ethyl]-piperazin-1-yl}-1-(4-chloro- benzyl)-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)- acetamide

N-[1-(4-Chloro-benzyl)-2-(4- dicyclohexylmethyl-piperazin-1-yl)-2-oxo-ethyl]-2-(2,3-dihydro- 1H-isoindol-1-yl)-acetamide

[0597] More preferred is a compound selected from the group consistingof:

[0598] “A” isomer#2

[0599] Isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[2diethylamino-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide,

[0600] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1-(2-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide,

[0601] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1-(2,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide,

[0602] “A” isomer#2

[0603]N-(1-(4-Chloro-benzyl)-2-{4-[2-diethylamino-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide,

[0604] “A” isomer#2

[0605]N-(1-(4-Chloro-benzyl)-2-{4-[1-(2-chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide,

[0606] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-(2-dipropylamino-1-phenyl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide,

[0607] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide,

[0608] “A” isomer #2

[0609]2-{4-[3-(4-Chloro-phenyl)-2-(2-2,3-dihydro-1H-isoindol-1-yl-acetylamino)-propionyl]-piperazin-1-yl}-N,N-diethyl-2-(2-fluoro-phenyl)-acetamide,

[0610]N-{1-(4-Chloro-benzyl)-2-[4-(1-isobutyl-3-methyl-butyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide,

[0611]N-(1-(4-Chloro-benzyl)-2-{4-[1-cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide,

[0612] “A” isomer#2, “C” isomer#2

[0613] 1,1-Dimethyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide,

[0614]3-(4-Chloro-phenyl)-1-{4-[2-diethylamino-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-[(1,2,3,4-tetrahydro-isoquinolin-3-ylmethyl)-amino]-propan-1-one,

[0615] “A” isomer#2, “C” isomer#2

[0616]N-(1-(4-Chloro-benzyl)-2-{4-[1-(2-chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2-methyl-2,3-dihydro-1H-isoindol-1-yl)-acetamide,

[0617] 7-Fluoro-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-behzyl)-2-[4-(2-diethylamino-1-phenyl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide,

[0618] “A” isomer#2, “C” isomer#2

[0619]N-(1-(4-Chloro-benzyl)-2-{4-[1-(2-chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamide,

[0620] “A” isomer#2, “C” isomer#1

[0621]N-(1-(4-Chloro-benzyl)-2-{4-[2-diethylamino-1-(2-fluorophenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(1-methyl-2,3-dihydro-1H-isoindol-1-yl)-acetamide,

[0622] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[1-(2-fluoro-phenyl)-2-methanesulfonylamino-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide,

[0623] “A” isomer#2, “C” isomer#2

[0624]N-(1-(4-Chloro-benzyl)-2-{4-[2-(ethyl-methanesulfonyl-amino)-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide,

[0625] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid[2-{4-[2-(acetyl-methyl-amino)-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-1-(4-chloro-benzyl)-2-oxo-ethyl]-amide,

[0626][2-(4-{3-(4-Chloro-phenyl)-2-[(1,2,3,4-tetrahydro-isoquinoline-3-carbonyl)-amino]-propionyl}-piperazin-1-yl)-2-(2-fluoro-phenyl)-ethyl]-ethyl-carbamicacid methyl ester,

[0627]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide,

[0628] “C” isomer#2

[0629]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide,and

[0630] “C” isomer#2

[0631]N-(1-(4-chloro-benzyl)2-{4-[1-cyclohexyl-2-(2,5-dioxo-pyrrolidin-yl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide,and pharmaceutically acceptable salt, stereoisomer and solvate thereof.

Preparation of the Compounds of the Invention

[0632] The preparation of the compounds of the present invention may becarried out via sequential or convergent synthetic routes. The skilledartisan will recognize that the three domains of a compound of formula Ior II are connected via amide bonds. The skilled artisan can, therefore,readily envision numerous routes and methods of connecting the threedomains via standard peptide coupling reaction conditions.

[0633] The phrase “standard peptide coupling reaction conditions” meanscoupling a carboxylic acid with an amine using a activating agent suchas EDC, DCC, and HATU, in an inert solvent such as DCM, in the presenceof a catalyst such as HOBT. The uses of protective groups for amine andcarboxylic acids to facilitate the desired reaction and minimizeundesired reactions are well documented. Conditions required to removeprotecting groups which may be present can be found in Greene, et al.,Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., NewYork, N.Y. 1991. CBZ and BOC protecting groups are used extensively inthe synthesis, and their removal conditions are known to those skilledin the art. For example, removal of CBZ groups can he achieved bycatalytic hydrogenation with hydrogen in the presence of a noble metalor its oxide such as palladium on activated carbon in a protic solventsuch as ethanol. In cases where catalytic hydrogenation iscontraindicated by the presence of other potentially reactivefunctionality, removal of CBZ groups can also be achieved by treatmentwith a solution of hydrogen bromide in acetic acid. Removal of BOCprotecting groups is carried out in a solvent such as DCM, methanol, orethyl acetate, with a strong acid, such as TFA, HCl, or HCl gas.

[0634] However prepared, the compound of formula I or II, when existingas a diastereomeric mixture, may be separated into diastereomeric pairs,for example, by fractional crystallization from a suitable solvent, forexample methanol or ethyl acetate or a mixture thereof. The pair ofenantiomers thus obtained may be separated into individual stereoisomersby conventional means, for example by the use of an optically activeacid as a resolving agent. Alternatively, any enantiomer of a compoundof the formula I may be obtained by stereospecific synthesis usingoptically pure starting materials or reagents of known configuration.Additionally, any enantiomer of a compound may be separated by chiralchromatography.

[0635] The A domains of the present invention, in general, may beprepared from commercially available starting materials via knownchemical transformations. For example, the synthesis of certain “A”domains of the present invention is illustrated by Schemes 1-2 below.

[0636] As shown in Scheme 1 and 2, synthesis of the internal amide “A”domains may begin with the appropriate esters of compound 1. Compound 1may be brominated with N-bromosuccinimide or treated with LDAA, followedby quenching with bromine, to yield α-bromo esters of compound 2.Compound 3 examples were prepared by reacting compound 2 with N-Bocpiperazine and potassium carbonate. Saponification of the ester, withbases such as NaOH, in EtOH, yielded the acids of compound 4. Dialkylamides of compound 5, were prepared from compound 4, the appropriateamine and coupling agents such as diethyl cyanophosphonate or EDC. Theamides could then be deprotected with TFA to yield compound 6, oralkylated a to the amide (compound 5A), followed by deprotection. Thepiperazine amines of compound 6 were then coupled to the appropriate BCdomains using standard coupling reagents such EDC or HATU.

[0637] Specifically, the A domain of certain compounds of the inventionmay be prepared as shown in Scheme 3 below.

[0638] To the appropriately substituted benzyl nitrile or ester, (1) or(2) in Scheme 3, was added N-bromosuccinimide to form the benzyl bromideor other halide derivative, 3 or 4. The halides are then subjected todisplacement reactions with N-Boc-piperazine to form compounds 6 or 7respectively. Alternatively, compound 6 or 7 could be formed from aStrecker synthesis using compound 5 and the appropriately protectedpiperazine derivative.

[0639] Certain compounds of the invention may also be prepared followinga scheme such as Scheme 4 below:

[0640] The nitrile of 6, scheme 4, may be reduced with LAH or othersuitable reducing agent to form the primary amine (7). This amine couldthen be bis-alkylated, followed by protecting group removal, to form(16) or (17). The primary amine (7) may also be acylated or sulfonylatedto form (9) or (10), respectively. The sulfonylated amine (10) could bealkylated to form (13), and the acylated compound (9) could be reduced,followed by sulfonylation, to form (14). Compounds of formula 9, 10, 13,and 14 may be deprotected to afford compounds of formula 11, 12, 13, and15 respectively. Unless otherwise indicated, reagents and procedures foreffecting the reactions described herein are known to one of skill inthe art and may be found in general reference texts such as AdvancedOrganic Chemistry by J. March, 5^(th) edition, Wiley IntersciencePublishers, New York, N.Y., and references therein.

[0641] Scheme 5 shows a method for resolving enantiomers formed by theA-domain pieces of compounds of formula I

[0642] Chiral resolution of the appropriately substituted phenyl glycinederivative, i.e. compound (8) scheme 5, may be accomplished by formationof the phthalimide (22) followed by chiral chormatography. The fastereluting isomers are labelled isomer 1 and the next eluting isomer 2.Methods for preparing phthalimide derivatives of primary amine viaphthalic anhydride are known to one of skill in the art. Similarly,protocols for chiral chromatography and other resolution methods areknown to one of skill in the art.

[0643] An alternate protocol for preparing the non-glycine derivativeA-domain is shown in scheme 6 below:

[0644] For example,the diakyl piperazine derivatives, (26) or (27)scheme 6, are prepared from a Grignard addition to the nitrile (25). Thenitrile (25), in turn, may be generated from a Strecker reaction withthe appropriate alkyl aldehyde i.e. compound (24) and N-Boc piperazine.

[0645] An alternative protocol for preparing the A-domain is shown inscheme 7 below:

[0646] As shown in Scheme 7, an appropriately substituted ester i.e.compound (28) may be brominated using an N-bromosuccinimide (NBS)protocol to afford compound (29). The bromide of (29) is displaced withBoc-piperazine to yield the “A” domain ester (30). The ester (30) isthen hydrolyzed to give the carboxylic acid, which is subsequentlytreated with the appropriate amine using standard amide formingprocedures to form the dialkyl amide (32). The amide (32) may be reducedto yield the dialkyl amine (31). The bromination, piperazinedisplacement and alkylation protocols are known to one of skill in theart.

[0647] Compounds containing saturation in the A-domain can be preparedas follows as shown in the general Scheme 8 below:

[0648] Synthesis begins with bromination of the commercially availablecyclohexyl acetic acid, which provides the corresponding a-bromoderivative. This material can be reacted with a mono-protectedpiperazine to afford an apiperazino ester. The ester moiety in thismolecule can be reduced to the primary alcohol and then coupled withphthalimide under standard reaction conditions known to one of skill inthe art. Alternatively, the phthalimido compound can be fashioned fromthe a-piperazino ester first by reduction to the aldehyde, followed byoxime formation, reduction to the amine, and condensation with phthalicanhydride. This intermediate is easily resolved into each antipode withchiral chromatography. Liberation of the amine by reducing thephthalimido intermide with excess hydrazine, followed by furtherfunctionalization provides acyl, sulfonyl, alkyl-acyl, alkyl-sulfonyl,and imide derivatives. These materials in turn are converted to thedesired final products by coupling to the B and C fragments withstandard peptide coupling methods. The reaction protocols describedherein are known to one of skill in the art, are found in standardorganic chemistry reference texts (i.e. J. March, supra), and aredescribed in the experimental section.

[0649] Compounds that contain homologues of aryl glycine can be preparedin a similar fashion by starting with homologues of phenylacetic acid.Bromination affords the α-bromo material (homologue of phenyl aceticacid), which can be reacted with piperazine derivatives giving theα-piperizino acid derivatives. These materials can be converted to thedesired amine substituted materials with protocols similar to the onesdescribed for the saturated analogs described above. Details of theabove procedures are found in the experimental section and also instandard reference texts.

[0650] “A” domain pieces wherein “y” is 1, or 2 are prepared utilizingthe corresponding mono-Boc-homopiperazine analog i.e. diazepine when yis 2. This results in the corresponding “A” domain piece when reactedwith an α-bromo material. The A-domain piece is processed further toobtain compounds of formula I or II-as described for the piperazine “A”domain compounds herein.

[0651] The “B” domain piece as used herein may be purchased, or preparedfrom readily available starting materials. A preferred “B” domain pieceis 4-chloro-D-Phe available commercially.

[0652] The present invention also provides novel processes for preparingcertain intermediates and/or compounds of the invention. For example aconvergent synthesis of a key intermediate isoindoline (5) (see Scheme 9below) via a Heck coupling, followed by a reductive amination, a ringcyclization and a resolution has been developed. Also, alternateasymmetric approaches including asymmetric Michael addition andasymmetric hydrogenation have also been developed to prepare compoundsof the invention and/or intermediates thereof.

[0653] As shown in scheme 9, the isoindoline compounds of the presentinvention may be prepared from 2-halobenzaldehyde 1 or substitutedanalog thereof (scheme 9) Preferred starting material is2-bromobenzaldehyde or substituted analog thereof. Pd-mediated Heckcoupling of 2-bromobenzaldehydes 1 with for example, methyl acrylate,provided α,β-unsaturated methyl esters 2, which undergoes reductiveamination to give amines (or carbamates where R₁ is for example, Boc) 3.Various Heck coupling reagents and conditions were found suitable toeffect the coupling reaction. Useful catalyst and ligands includePd(OAc)₂/PPh₃, Pd(OAc) PPh₃/BU₄NBr, Pd(PPH₃)₂Cl₂/CUI,Pd(OAC)₂/P(O-Tol)₃. Suitable solvent or solvent systems for the Heckcoupling reaction include DMF, toluene and ethyl acetate. Most preferredbase is triethylamine.

[0654] Reductive amination of the aldehyde functionality of 2 to aminesis accomplished in good yields by reaction with benzylamine orα-methylbenzylamine in acidic conditions, followed by in situ reductionof the incipient imines with NaCNBH₃ at about pH 5. Other reducingagents including Na(OAc)₃BH and NaBH₄/H may also be used to effectreduction of the incipient imines. Interestingly, the resulting aminesimmediately cyclized to the isoindoline compounds under the same acidicconditions conditions for the reduction. Direct preparation of compound4 may also be effected by use of BocNH₂ instead of benzylamine in thereductive amination step. Screening of various reducing agentsdemonstrated that the combination of Et₃SiH and TFA in CH₃CN representsthe preferred method for effecting reductive amination using BocNH₂.

[0655] The N-Boc isoindolinecarboxylic acid 5 may also be prepared from3 as the carbamate, by an intra-molecular Michael addition and esterhydrolysis. The resolution of the isoindolinecarboxylic acids 4 bycrystallization afforded enantio-pure compounds 5.

[0656] Two alternate asymmetric approaches have also been developed forthe synthesis of isoindolinecarboxylic acid 5 i.e. asymmetric Michaeladditions and asymmetric hydrogenation. In the asymmetric Michaeladdition approach, a-methylbenzyl amine is used as a chiral auxiliary toinduce the enantio-selectivity. In the asymmetric hydrogenationapproach, compound 4′ could be converted to 5 stereoselectively in thepresence of chiral ligands.

[0657] Finally the coupling of the isoindolines 5 with the “B” domainpiece, i.e. D-Cl-Phe to afford compound 6 (“BC” piece) is accomplishedby standard amino acid coupling reactions such as, for example, by theuse of EDC or EDCI or other activating agents in the presence ofsuitable is dimethylaminopyridine (DMAP). The product (6) is thencoupled with an “A” domain piece such as for example,4-[2-Amino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (compound 207, table V), as discussed herein to affordthe target MC₄R agonist compound of formula I by coupling reactionsknown to one of skill in the art.

[0658] Preferably, the isoindole or other “C” domain piece is coupled toan “AB” coupled domain piece to form the compound of formula I.

[0659] As shown in Scheme 10, m-tyrosine ester or analogs, includingsubstituted analogs thereof, may be esterified by forming the acidhalide followed by nucleophilic displacement of halide by the alkoxygroup from an alcohol, i.e. methanol or ethanol. Where thionyl chlorideor other halide source is used the product may be isolated as the acidaddition salt (2). The resulting ester (2) is subjected to aPictet-Spengler reaction by heating with a suitable ketone or aldehydein refluxing conditions. For example, an unsubstituted isoquinolinebackbone (3) may be formed by employing formaldehyde in thepictet-Spengler reaction. On the other hand, a gem-dimethyl substitutedisoquinoline wherein R¹¹ is methyl, may be formed by using acetone asthe ketone source and solvent. Other less reactive substituents may besubstituted as the R11 group for the practice of the present invention.The product isoquinoline (3) may be isolated preferably as the acidaddition salt. Where m-tyrosine is used as the starting material, thefree hydroxyl group is removed first by protection/activation with agood leaving group such as, for example, reaction with triflic anhydride(trifluoromethane sulfonic anhydride) or methanesulfonic acid to formthe triflate or mesylate in the presence of a base. The triflate is apreferred group used to set up the compound (3) for deoxygenationbecause of the extra electron withdrawing effect of the trifluoromethanesubstituent. The deoxygenation reaction is effected by hydrogenation atpressures of about 50psi. The product (4) may be isolated as the acidaddition salt. The product (4) is hydrolyzed under basic conditions toafford the acid salt. Suitable bases for the above hydrolysis includeaqueous sodium hydroxide, potassium hydroxide and sodium lithiumhydroxide. The reaction is preferably performed in a mixture of aqueousand organic solvents. An exotherm during addition of base may beregulated (i.e. less than about 35° C.) to avoid overheating or “runawayreactions.” The reaction product may be isolated by aqueous work up.Alternatively, the entire mixture may be concentrated and washed withorganic solvents to afford the desired product (6) aftercrystallization.

[0660] The product (6) is then reacted with a “B” domain substrate suchas, for example, 4-chloro-D-phenylalanine as described previously and inthe experimental section. The resulting “BC” combination product is thenreacted with an “A” domain piece such as, for example,4-[2-Amino-1-(2fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (compound 207, table V) to form the respective compoundof formula I. Alternatively, the product (6) may be reacted with an“AdB” domain combination product to afford a compound of formula I.

[0661] One of skill is aware that certain protections and deprotectionsof intermediates in Scheme 10, to form the carbamate, substituted amineor free amine at the isoquinolinyl nitrogen are possible andcontemplated as within the scope of this invention. Unless otherwisespecified, reagents and procedures for effecting the reactions describedherein are known to one of skill in the art and may be found in generalreference texts such as Advanced Organic Chemistry by J. March, 5^(th)edition, Wiley Interscience Publishers, New York, N.Y., and referencestherein.

[0662] In an alternate procedure, the isoquinoline product i.e. compound(3) or (5) including their N-protected analogs may be resolved byreaction with a resolving agent .such as for example, L-tartaric acid,dehydroabietylamine or other resolving agents known to one of skill inthe art.

[0663] Alternatively, asymmetric analogs of product (6) may be preparedby using asymmetric starting materials. For example, L-DOPA may be usedin place of m-tyrosine ester in reactions essentially similar to thosedescribed and illustrated in Scheme 10, and in the examples, to affordthe asymmetric analog of compound (6).

[0664] Tetrahydroisoquinoline acetic acid derivatives may be preparedand utilized as shown in Scheme 10a below:

[0665] As shown in Scheme 10a, a compound of formula 10a wherein X ishalogen, preferably bromo or chloro, and R and R¹¹ are as definedpreviously, and which is obtained commercially or prepared fromcommercial starting materials is reacted with cyanomethylethylacetate toafford a compound of formula 10b. The compound of formula 10b may beprotected as the compound 10c with a suitable protecting group (Pg) andthen subjected to hydrogenation conditions including for exampleasymmetric hydrogenation to form a compound of formula lod which may bechiral (depending on hydrogenation conditions, i.e.asymmetric versusnon-assymetric hydrogenation). The compound of formula 10d orstereoisomer thereof, is reacted with a B-domain piece such as, forexample, 4-chloro-D-phe to afford a BC piece (10e). The compound offormula 10e is then reacted with an A-domain piece to afford a compoundof formula I. The details of the specific reaction steps are similar toor analogous to reactions taught herein, and in the experimentalsection. Furthermore, one of skill in the art is aware of that suchintermediate reactions as hydrolysis and deprotection may be necessaryto achieve optimum yields in certain steps of the scheme as shown. Oneof skill in the art is also aware of further common manipulations suchas N-alkylation, or N-acylation, and alkylations on the benzene ring toafford other compounds of formula I.

[0666] Formulation

[0667] The compound of formula I or II is preferably formulated in aunit dosage form prior to administration. Therefore, yet anotherembodiment of the present invention is a pharmaceutical compositioncomprising a compound of formula I or II and one or morepharmaceutically acceptable carriers, diluents or excipients.

[0668] The present pharmaceutical compositions are prepared by knownprocedures using well-known and readily available ingredients. In makingthe formulations of the present invention, the active ingredient(formula I or II compound) will usually be mixed with a carrier, ordiluted by a carrier, or enclosed within a carrier which may be in theform of a capsule, sachet, paper or other container. When the carrierserves as a diluent, it may be a solid, semisolid or liquid materialwhich acts as a vehicle, excipient or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosol (as a solid or in a liquid medium), soft and hardgelatin capsules, suppositories, sterile injectable solutions andsterile packaged powders.

[0669] Some examples of suitable carriers, excipients, and diluentsinclude lactose, dextrose, sucrose, sorbitol, mannitol, starches, gumacacia, calcium phosphate, alginates, tragacanth, gelatin, calciumsilicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose,water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc,magnesium stearate and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents or flavoring agents. Thecompositions of the invention may be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient.

[0670] Dose

[0671] The specific dose administered is. determined by the particularcircumstances surrounding each situation. These circumstances include,the route of administration, the prior medical history of the recipient,the pathological condition or symptom being treated, the severity of thecondition/symptom being treated, and the age and sex of the recipient.However, it will be understood that the appropriate caregiver in lightof the particular circumstances of the patient or recipient willdetermine the therapeutic dosage administered.

[0672] Generally, an effective minimum daily dose of a compound offormula I or II is about 1, 5, 10, 15, or 20 mg. Typically, an effectivemaximum dose is about 500, 100, 60, 50, or 40 mg. The exact dose may bedetermined, in accordance with the standard practice in the medical orveterinary arts of “dose titrating” the recipient; that is, initiallyadministering a low dose of the compound, and gradually increasing thedoes until the desired therapeutic effect is observed.

[0673] Route of Administration

[0674] The compounds may be administered by a variety of routesincluding the oral, rectal, transdermal, subcutaneous, topical,intravenous, intramuscular or intranasal routes.

[0675] Combination Therapy

[0676] Compounds of Formula I or II may be used in combination withother drugs that are used in the treatment of the diseases or conditionsfor which compounds of formula I or II are useful. Such other drugs maybe administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of formula I or II.When a compound of formula I or II is used contemporaneously with one ormore other drugs, a pharmaceutical composition containing such otherdrugs in addition to the compound of formula I or II is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of formula I. Examples of other activeingredients that may be combined with a compound of formula I or II,either administered separately or in the same pharmaceuticalcompositions, include, but are not limited to:

[0677] (a) insulin sensitizers including (i) PPARγ agonists such as theglitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555,BRL49653 and the like), and compounds disclosed in WO97/27857, 97/28115,97/28137 and 97/27847; (ii) biguanides such as metformin and phenformin;

[0678] (b) insulin or insulin mimetics;

[0679] (c) sulfonylureas such as tolbutamide and glipizide;

[0680] (d) alpha glucosidase inhibitors (such as acarbose),

[0681] (e) cholesterol lowering agents such as (i) HMG-CoA reductaseinhibitors (lovastatin, simvastatin and pravastatin, fluvastatin,atorvastatin, and other statins), (ii) sequestrants (cholestyramine,colestipol and a dialkylaminoalkyl derivatives of a cross-linkeddextran), (iii) nicotinyl alcohol nicotinic acid or a salt thereof, (iv)proliferator-activater receptor alpha agonists such as fenofibric acidderivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), *(v)inhibitors of cholesterol absorption for example beta-sitosterol and(acyl CoA:cholesterol acyltransferase) inhibitors for examplemelinamide, (vi) probucol, (vii) vitamin E, and (viii) thyromimetics;

[0682] (f) PPARδ agonists such as those disclosed in WO97/28149;

[0683] (g) antiobesity compounds such as fenfluramine, dexfenfluramine,phentermine, sibutramine, orlistat, and other beta-3 adrenergic receptoragonists such as those described in U.S. patent application Ser. Nos.60/217,965, 60/241,614 and 60/247,304;

[0684] (h) feeding behavior modifying agents such as neuropeptide Yantagonists (e.g. neuropeptide Y5) such as those disclosed in WO97/19682, WO 97/20820, WO 97/20821, WO 97/20822 and WO 97/20823;

[0685] (i) PPAR alpha agonists such as described in WO 97/36579 byGlaxo;

[0686] (j) PPARγ antagonists as described in WO97/10813;

[0687] (k) serotonin reuptake inhibitors such as fluoxetine andsertraline;

[0688] (l) growth hormone secretagogues such as MK-0677; and

[0689] (m) agents useful in the treatment of male and/or female sexualdysfunction such as phosphodiester V inhibitors such as sildenafil andICI-351, and alpha-2 adrenergic receptor antagonists, such asphentolamine mesylate; and dopamine-receptor agonists, such asapomorphine.

[0690] Demonstration of Function

[0691] A. Binding Assay. The radioligand binding assay is used toidentify competitive inhibitors of ¹²⁵I-NDP-alpha-MSH binding to clonedhuman MCRs using membranes from stably transfected human embryonickidney (HEK) 293 cells.

[0692] HEK 293 cells transfected with human or rat melanocortininreceptors are grown either as adherent monolayers or suspension culture.Monolayer cells are grown in roller bottle cultures at 37° C. and 5%CO₂/air atmosphere in a 3:1 mixture of Dulbecco's modified Eagle medium(DMEM) and Ham's F12 containing 25 mM L-glucose, 100 units/ml penicillinG, 100 microgram/ml streptomyocin, 250 nanogram/ml amphoterin B, 300microgram/ml genticin and supplemented with 5% fetal bovine serum.Monolayer cells are adapted to suspension culture (Berg et al.,Biotechniques Vol. 14, No.6, 1993) and are grown in spinner or shakerflasks (37° C. and 7.5% CO₂/air overlay) in a modified DME/F12 mediumcontaining 0.1 mM CaCl₂, 2% equine serum and 100 microgram/ml sodiumheparin (to prevent cell-cell aggregation). Cells are harvested bycentrifugation, washed in PBS, and pellets are stored frozen at −80° C.until membrane preparations.

[0693] The cell pellets are resuspended in 10 volumes of membranepreparation buffer (i.e., 1 g pellet to 10 ml buffer) having thefollowing composition: 50 mM Tris pH 7.5 @ 4° C., 250 mM sucrose, 1 mMMgCl₂, Complete® EDTA-free protease inhibitor tablet (BoehringerMannheim), and 24 micrograms/ml DNase I (Sigma, St. Louis, Mo.). Thecells are homogenized with a motor-driven dounce using 20 strokes, andthe homogenate is centrifuged at 38,000×g at 4° C. for 40 minutes. Thepellets are resuspended in membrane preparation buffer at aconcentration of 2.5-7.5 mg/ml and 1 milliliter aliquots of membranehomogenates are quickly frozen in liquid nitrogen and then stored at−80° C.

[0694] Solutions of a compound of formula I (300 picomolar to 30micromolar) or unlabelled NDP-alpha-MSH (1 picomolar to 100 nanomolar)are added to 150 microliters of membrane binding buffer to yield finalconcentrations (listed in parantheses). The membrane binding buffer hasthe following composition: 25 mM HEPES pH 7.5; 10 mM CaCl₂; 0.3% BSA).One hundred fifty microliters of membrane binding buffer containing0.5-5.0 microgram membrane protein is added, followed by 50 nanomolar¹²⁵I-NDP-alpha-MSH to final concentration of 100 picomolar.Additionally, fifty microliters of SPA beads (5 mg/ml) are added and theresulting mixture is agitated briefly and incubated for 10 hours at roomtemperature. The radioactivity is quantified in a Wallac TriluxMicroplate Scintillation counter. IC₅₀ values obtained in competitionassays are converted to affinity constants (K_(i) values) using theCheng-Prusoff equation: K_(i)=IC₅₀/(1+D/K_(d)).

[0695] B. Functional assays. Functional cell based assays are developedto discriminate agonists and antagonists.

[0696] Agonist Assay: HEK 293 cells stably expressing a humanmelanocortin receptor (see e.g., Yang, et al., Mol-Endocrinol., 11(3):274-80, 1997) are dissociated from tissue culture flasks using atrypsin/EDTA solution(o.25%; Life Technologies, Rockville, MD). Cellsare collected by centrifugation and resuspended in DMEM (LifeTechnologies, Rockville, Md.) supplemented with 1% L-glutamine and 0.5%fetal bovine serum. Cells are counted and diluted to 4.5×10⁵/ml.

[0697] A compound of formula I is diluted in dimethylsulfoxide (DMSO)(3×10⁻⁵ to 3×10⁻¹⁰ M final concentrations) and 0.05 volume of compoundsolution is added to 0.95 volumes of cell suspension; the final DMSOconcentration is 0.5%. After incubation at 37° C./5% CO₂ for 5 hours,cells are lysed by addition of luciferin solution (50 mM Tris, 1 mMMgCl₂, 0.2 % Triton-X100, 5 mM DTT, 500 micromolar Coenzyme A, 150micromolar ATP, and 440 micromolar luciferin) to quantify the activityof the reporter gene luciferase, an indirect measurement ofintracellular cAMP production.

[0698] Luciferase activity is measured from the cell lysate using aWallac Victor 2 luminometer. The amount of lumen production whichresults from a compound of formula I is compared to that amount oflumens produced in response to NDP- alpha-MSH, defined as a 100%agonist, to obtain the relative efficacy of a compound. The EC₅₀ isdefined as the compound concentration that results in half maximalstimulation, when compared to its own maximal level of stimulation.

[0699] Melanocortin Receptor Whole Cell cAMP Accumulation Assay

[0700] Compound Preparation:

[0701] In the agonist assay, compounds are prepared as 10 mM andNDP-aMSH (control) as 33.3 μM stock solutions in 100% DMSO. These areserially diluted in 100% DMSO. The compound plate is further diluted1:200 in compound dilution buffer (HBSS092, 1 mM Ascorbic Acid, 1 mMIBMX, 0.6% DMSO, 0.1% BSA). The final concentration range being 10μM-100 pM for compound and 33.33 nM-0.3 pM for control in 0.5% DMSO.Transfer 20 μl from this plate into four PET 96-well plates (all assaysare performed in duplicate for each receptor).

[0702] Cell Culture and Cell Stimulation:

[0703] HEK 2.93 cells stably transfected with the MC₃R and MC₄R weregrown in DMEM containing 10% FBS and 1% Antibiotic/Antimycotic Solution.On the day of the assay the cells were dislodged with enzyme free celldissociation solution and resuspended in cell buffer (HBSS-092, 0.1%BSA, 10 mM HEPES) at 1×e6 cells/ml. Add 40 μl of cells/well to the PET96-well plates containing 20 ul diluted compound and control. Incubate @37° C. in a waterbath for 20 minutes. Stop the assay by adding 50 μlQuench Buffer (50 mM Na Acetate, 0.25% Triton X-100).

[0704] Radioligand Binding Assays:

[0705] Radioligand binding assays were run in SPA buffer (50 mM SodiumAcetate, 0.1% BSA). The beads, antibody and radioligand were diluted inSPA buffer to provide sufficient volume for each 96-well plate. To eachquenched assay well was added 100 ul cocktail containing 33.33 ul ofbeads, 33.33 μl antibody and 33.33 μl ¹²⁵I-cAMP. This was based on afinal concentration of 6.3 mg/ml beads, 0.65% anti-goat antibody and 61pM of ¹²⁵I-cAMP (containing 25000-30000 CPM) in a final assay volume of210 μl. The plates were counted in a Wallac MicroBeta counter after a12-hour incubation.

[0706] The data was converted to pmoles cAMP using a standard curveassayed under the same conditions. The data was analyzed using ActivityBase software to generate agonist potencies (EC₅₀) and percent relativeefficacy data to NDP-aMSH.

[0707] C. In vivo food intake models.

[0708] 1) overnight food intake. Sprague Dawley rats are injectedintracerebroventricularly with a test compound in 400 nL of 50%propylene glyco/artificial cerebrospinal fluid one hour prior to onsetof dark cycle (12 hours). Food intake is determined using a computerizedsystem in which each rat's food is placed on a computer monitoredbalance. Cumulative food intake for 16 hours post compoundadministration is measured.

[0709] 2) Food intake in diet induced obese mice. Male C₅₇/B16J micemaintained on a high fat diet (60% fat calories) for 6.5 months from 4weeks of age are dosed intraperitoneally with a compound of formula I orII. Food intake and body weight are measured over an eight day period.Biochemical parameters relating to obesity, including leptin, insulin,triglyceride, free fatty acid, cholesterol and serum glucose levels aredetermined.

[0710] D. Rat Ex Copula Assay

[0711] Sexually mature male Caesarian Derived Sprague Dawley (CD) rats(over 60 days old) are used with the suspensory ligament surgicallyremoved to prevent retraction of the penis back into the penile sheathduring the ex copula evaluations. Animals receive food and water ad liband are kept on a normal light/dark cycle. Studies are conducted duringthe light cycle.

[0712] 1) Conditioning to Supine Restraint for Ex Copula Reflex Tests.This conditioning takes about 4 days. Day 1, the animals are placed in adarkened restrainer and left for 15-30 minutes. Day 2, the animals arerestrained in a supine position in the restrainer for 15-30 minutes. Day3, the animals are restrained in the supine position with the penilesheath retracted for 15-30 minutes. Day 4, the animals are restrained inthe supine position with the penile sheath retracted until penileresponses are observed. Some animals require additional days ofconditioning before they are completely acclimated to the procedures;non-responders are removed from further evaluation. After any handlingor evaluation, animals are given a treat to ensure positivereinforcement.

[0713] 2) Ex Copula Reflex Tests. Rats are gently restrained in a supineposition with their anterior torso placed inside a cylinder of adequatesize to allow for normal head and paw grooming. For a 400-500 gram rat,the diameter of the cylinder is approximately 8 cm. The lower torso andhind limbs are restrained with a non-adhesive material (vetrap). Anadditional piece of vetrap with a hole in it, through which the glanspenis will be passed, is fastened over the animal to maintain thepreputial sheath in a retracted position. Penile responses will beobserved, typically termed ex copulu genital reflex tests. Typically, aseries of penile erections will occur spontaneously within a few minutesafter sheath retraction. The types of normal reflexogenic erectileresponses include elongation, engorgement, cup and flip. An elongationis classified as an extension of the penile body. Engorgement is adilation of the glans penis. A cup is defined as an intense erectionwhere the distal margin of the glans penis momentarily flares open toform a cup. A flip is a dorsiflexion of the penile body.

[0714] Baseline and/or vehicle evaluations are conducted to determinehow and if an animal will respond. Someanimals have a long durationuntil the first response while others are non-responders altogether.During this baseline evaluation, latency to first response time, numberand type of responses are recorded. The testing time frame is 15 minutesafter the first response.

[0715] After a minimum of 1 day between evaluations, these same animalsare administered a compound of formula I at 20 mg/kg and evaluated forpenile reflexes. All evaluations are videotaped and scored later. Dataare collected and analyzed using paired 2 tailed t-tests to comparedbaseline and/or vehicle evaluations to drug treated evaluations forindividual animals. Groups of a minimum of 4 animals are utilized toreduce variability.

[0716] Positive reference controls are included in each study to assurethe validity of the study. Animals can be dosed by a number of routes ofadministration depending on the nature of the study to be performed. Theroutes of administration includes intravenous (IV), intraperitoneal(IP), subcutaneous (SC) and intracerebral ventricular (ICY).

[0717] E. Models of Female Sexual Dysfunction

[0718] Rodent assays relevant to female sexual receptivity include thebehavioral model of lordosis and direct observations of copulatoryactivity. There is also a urethrogenital reflex model in anesthetizedspinally transected rats for measuring orgasm in both male and femalerats. These and other established animal models of female sexualdysfunction are described in McKenna, et al., Am. J. Physiol.,(Regulatory Integrative Comp. Physiol 30):R1276-R1285, 1991; McKenna, etal., Pharm. Bioch. Behav., 40:151-156, 1991; and Takahashi, et al.,Brain Res., 359:194-207, 1985.

Results

[0719] Sample assay results showing the MC₄ agonist potency (EC₅₀), MC₄binding and relative efficacy of compounds of the present invention isprovided in the results table below: Results: Compd# or MC4 BindingRelative Example# Ki (nM) MC4 EC₅₀ (nM) Eff. Example N38 10.0 69.3 115.6Example N71 11.3 8.4 102.6 Compd 814 18.1 127.0 108.6 Compd 3251 5.876.7 67.0

Experimental Section

[0720] The following abbreviations have been used in this applicationfor brevity: BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl Boct-butoxycarbonyl CBZ benzyloxycarbonyl DCM (MeCl₂) dichloromethane DEADdiethyl azodicarboxylate DIPEA diisopropylethylamine (also DIEA) DMAP4-dimethylamino pyridine DMF N,N-dimethylformamide DMSOdimethylsulfoxide aq. aqueous eq. equivalent(s) EDC1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl ESI-MS electron sprayion-mass spectroscopy Et ethyl EtOAc ethyl acetate HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′ tetramethyluroniumhexafluorophosphate HOAT: 1-hydroxy-7-azabenzotriazole HOBT1-hydroxybenzotriazole hydrate HPLC high performance liquidchromatography HRMS high resolution mass MS mass spectroscopy LRMS lowresolution mass Me methyl Ms methylsulfonyl Pd₂(dba)₃tris(dibenzylideneacetone)-dipalladium(0) Ph phenyl Phe phenylalanine Prpropyl TBS tertbutyldimethylsilyl TFA trifluoroacetic acid TEAtriethylamine THF tetrahydrofuran Tic1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid TLC thin-layerchromatography h hour rt room temperature (also RT or r.t.)

[0721]

[0722] The following experimentals describe the synthesis of mc4agononists of the above motif where an “a” domain is linked by an amidebond to a “b” domain which is connected by an amide or amine linkage toa “c” domain.

[0723] Compounds 1-19 (listed in Table I. below) were preparedsubstantially analogous to the following procedures from the respectivecommercially available materials.

Procedure A

[0724] Preparation of Bromo-(2-chloro-phenyl)-acetonitrile (1). To asolution of 2-chlorobenzylcyanide (1.0 g, 6.60 mmol) in CC₁ ₄ (25 mL)was added N-bromosuccinamide (1.29 g, 7.26 mmol) and2,2′-azobis-(2-methylpropionitrile) (0.05 g, 0.33 mmol). The reactionmixture was allowed to reflux for 48 h. The reaction mixture was thendiluted with EtOAc (50 mL) and washed with 0.1 M NaOH (50 mL). Theorganic phase was concentrated to dryness yielding 1.0 g (66%) product.

[0725] MS (ES) N/A (M+1)

Procedure C

[0726] Preparation of4-[Cyano-(2-fluoro-phenyl)-methyl]piperazine-1-carboxylic acidtert-butyl ester (7). To 2-fluorobenzaldehyde (10.0 g, 80.57 mmol) inether (10 mL) was added TMSCN (9.97 g, 100.72 mmol) followed by acatalytic amount of ZnI₂ and the solution was stirred while cooling withan ice bath as necessary until the catalyst dissolved andre-precipitated out. Boc-piperazine (14.9 g, 80.57 mmol) in MeOH (60 mL)was then added and the solution was allowed to stir at reflux for 4 hand then at room temperature for 18 h. The reaction mixture was thencooled to 0° C. and the product was collected by filtration.Concentration of the mother liquor and recrystallization from methanolprovided 20.0 g (78%) product.

[0727] MS N/A [M+1] TABLE I Prepared

Analogous

Cmpd. # Structure to Procedure

1

A N/A 2

A N/A 3

A N/A 4

C 368.1 5

A N/A 6

C N/A 7

C N/A 8

C N/A 9

C N/A 10

C N/A 11

C N/A 12

A N/A 13

A N/A 14

A N/A 15

A N/A 16

A N/A 17

A N/A 18

C 320.1 19

C 334.1

[0728] Compounds 101-110 (listed in Table III. below) were preparedutilizing substantially analogous procedures from the respectivebromobenzylnitriles.

Procedure B

[0729] Preparation of4-[(2-Chloro-phenyl)-cyano-methyl]-piperazine-1-carboxylic acidtert-butyl ester (101). To a solution ofbromo-(2-chloro-phenyl)-acetonitrile (1)(1.5 g, 6.45 mmol) in MeCN (25mL) was added K₂CO₃ (1.78 g, 12.91 mmol), piperazine-1-carboxylic acidtert-butyl ester (1.32 g, 7.10 mmol) and tetrabutylammonium iodide (0.02g, 0.06 mmol). The reaction mixture was allowed to reflux for 24 h. Thereaction mixture was then diluted with EtOAc (100 mL} and washed withbrine (100 mL). The organic phase was concentrated to dryness. The crudematerial was purified by chromatography (silica gel 60 mesh, elutingwith a gradient of 5% EtOAc in hexanes to 1:1 hexanes/EtOAc) yielding1.4 g (65%) of pure product.

[0730] MS (ES) 336.1 (M+1) TABLE III Cmpd.

Analogous # Structure

Procedure

101

B 336.1 102

B 336.1 103

B 336.1 104

B N/A 105

B 368.1 106

B 368.1 107

B 336.1 108

B 334.1 109

B N/A 110

B 334.1

[0731] Compounds 201-223 (listed in Table V. below) were preparedutilizing substantially analogous procedures for reduction of therespective nitriles, amides or phthalimide-protected amines.

Procedure D

[0732] Preparation of4-[2-Amino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (207). 1M LAH in THF (250 mL, 250 mmol) was cooled to−40° C. and 4-[Cyano-(2-fluoro-phenyl)-methyl]-piperazine-1-carboxylicacid tert-butyl ester (7) (20 g, 62.66 mmol) in THF (100 mL) was addedslowly via addition funnel. The reaction mixture was allowed to stir for2 h at −40° C. and then allowed to warm to 0° C. Reaction progress wasmonitored by H¹ NMR. The reaction mixture was then cooled to −40° C.again and H₂O (9.5 mL) was added. The reaction mixture was then dilutedwith THF (1 L) followed by the addition of 15% NaOH (9.5 mL) and H₂O(28.5 mL). The solution was then allowed to warm to room temperature.The aluminum salts were removed by filtration and the filtrate wasconcentrated to dryness. The resulting residue was taken up in EtOAc(500 mL) and H₂O (500 mL) and the aqueous layer was made acidic (pH=4)by cautious addition of a 25% aqueous solution of KHSO₄. The aqueousphase was then made basic (pH=10) with SN NaOH and the product wasextracted into EtOAc (500 ml) and concentrated to dryness. The startingmaterial (nitrile) can be recovered by concentration of the originalorganic phase and purified by recrystallization from MeOH. The yield was9.2 g (466) pure product.

[0733] MS (ES) 324.2 [M+1]

Procedure E

[0734] Preparation of4-[2-Amino-1-(2-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (201). To NaBH₄ (0.79 g, 20.84 mmol) in THF (20 mL) at0° C. was added TFA (2.38 g, 20.84 mmol) dropwise. To this cooledmixture was added4-[(2-Chloro-phenyl)-cyano-methyl)-piperazine-1-carboxylic acidtert-butyl ester (101) (1.40 g, 4.17 mmol) in THF (10 mL) dropwise. Thereaction mixture was allowed to stir at room temperature for 18 h. Thereaction was quenched with H₂O (50 mL) and diluted with EtOAc (100 mL).The organic phase was washed with H₂O (100 mL) and brine (100 mL). Thecrude material was purified by chromatography (silica gel 60 mesh,eluting with 10% TEA/10% MeOH in EtOAc) yielding 0.49 g (34%) pureproduct.

[0735] MS (ES) N/A [M+1]

Procedure G

[0736] Preparation of4-[2-Amino-1-(2-chloro-phenyl)-ethyl]piperazine-1-carboxylic acidtert-butyl ester (213). To4-[1-(2-Chloro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (302) (1.0 g, 2.15 mmol) in EtOH (5 mL) was addedhydrazine (0.67 mL, 21.5 mmol) and the solution was heated at 60° C. for1 h. The reaction mixture is then taken up in EtOAc (50 mL) and washedwith 1N NaOH (50 mL). The organic phase was concentrated to drynessyielding 0.73 g (100%) pure product.

[0737] MS (ES) 340.2 [M+1]

Procedure BB

[0738] Preparation of 4- [2-Amino-1-(4-methoxy-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (218). To asolution of4-[2-Amino-1-(4-methoxy-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (108) (1.01 g, 3.01 mmol) in 2M ammonia in methanol(100 mL) was added Raney nickel (0.50 g). The solution was allowed tostir at 40° C. under a hydrogen atmosphere (60 psi) for 18 h. Thereaction mixture was then filtered through Celite. The filtrate wasconcentrated to dryness. The crude material was purified bychromatography (silica gel 60 mesh, eluting with a gradient of % TEA/5%MeOH in EtOAc) yielding 0.38 g (38%) pure product.

[0739] MS (ES) 336.2 (M+1)

Procedure J

[0740] Preparation of4-[2-Amino-1-(2-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (212). To4-[Carbamoyl-(2-chloro-phenyl)-methyl]-piperazine-1-carboxylic acidtert-butyl ester 462(0.45 g, 1.27 mmol) in THF (10 mL) at 0° C. wasadded 1.0M BH₃ in THF (5.1 mL). The reaction was allowed to stir atreflux for 18 h. MeOH (5.0 mL) was added to the reaction mixture andmixture was then concentrated to dryness. The resulting residue wastaken up in MeOH (10 mL) and allowed to reflux for 1 h. The reactionmixture was concentrated to dryness and the resulting residue was takenup in EtOAc (30 mL) and washed with sat. NaHCO₃ (30 mL) and brine (30mL). The organic phase was concentrated to dryness yielding 0.18 g (43%)product.

[0741] 340.1[M+1] TABLE V

Cmpd.

Structure

201

E 340.1 202

E 340.1 203

E 340.1 204

E 374.2 205

BB 320.3 206

E N/A 207

D 324.2 208

G 324.2 “A”isomer #2 209

D 342.2 210

D 342.2 211

D 392.3 212

D 340.1 213

G 340.0 “A”isomer #2 214

G 374.1 “A”isomer #2 215

E 374.1 216

E 374.1 217

E 340.1 218

BB 336.2 219

E 320.2 220

BB 336.2 221

G 340.0 “A”isomer #1 222

G 275.1 223

G 338.1

[0742] Compounds 301-303 (listed in Table VI. below) were preparedsubstantially analogous to the following procedure F.

Procedure F

[0743] Preparation and resolution of4-[1-(2-Chloro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (302). To4-2[-amino-1-(2-chloro-phenyl)-ethyl]-1-Boc-piperazine (201) (4.34g,12.7 mmol) was added phthalic anhydride (1.89 g, 12.7 mmol). The mixturewas heated at 130° C. for 1 h and then allowed to cool to roomtemperature. The resulting solid was recrystallized from MeOH. Theenantiomers of the phthalimide-protected product were separated bychiral chromatography, using a Chiralcel OD (4.6×250 mm) column, elutingwith 5% 3A alcohol in heptane at 1 mL/min. The first eluting isomer waslabeled isomer #1 and the second eluting isomer #2. 5.6 g (95%) of themixture was isolated and separated.

[0744] MS (ES) 470.3 [M+1] INSERT TABLE VI

Cmpd.

# Structure

301

F 454.2 302

F 470.3 303

F 504.3

[0745] Compounds 351-352 (listed in Table VII. below) were preparedsubstantially analogous to the following procedure GG.

Procedure GG

[0746] Preparation of 4-(Carboxy-phenyl-methyl)-piperazine-1-carboxylicacid tert-butyl ester (351). To4-(Methoxycarbonyl-phenyl-methyl)-piperazine-1-carboxylic acidtert-butyl ester (151) (30.4 g, 87.25 mmol) in EtOH (200 mL) was addedof 1N NaOH (192 mL) and the reaction mixture was allowed to stir at roomtemperature for 18 h. The reaction mixture is then concentrated todryness. The resulting residue is taken up in H₂O and acidified slowlyat 0° C. with 10% NaSO₄ (pH=5-6). The desired product was then extractedinto EtOAc. The organic phase was then concentrated to dryness yielding24.3 g (86%) product.

[0747] MS (ES) 319.4 [M-1] TABLE VII

Cmpd. # Structure

351

GG N/A 352

GG N/A

[0748] Compounds 361 (listed in Table VIII. below) were preparedsubstantially analogous to the following procedure HH.

Procedure HH.

[0749] Preparation of4-(2-Hydroxy-1-phenyl-ethyl)-piperazine-1carboxylic acid tert-butylester (361). To 4-(Carboxy-phenyl-methyl)-piperazine-1-carboxylic acidtert-butyl ester (351) (10.7 g, 33.43 mmol) in THF (120 mL) at 0° C. wasslowly added BH₃-SMe₂ (6.69 mL, 66.86 mmol). The reaction mixture wasallowed to warm to room temperature and then stirred at room temperaturefor 96 h. The reaction mixture was then quenched with sat. NaHCO₃ (120mL) at 0° C. and diluted with Et₂O. The organic phase was dried withMgSO₄ and then concentrated to dryness. The crude material was purifiedby chromatography (silica gel 60 mesh, eluting with 50% EtOAc/50%hexanes); yielding 3.78 g (86%) pure product.

[0750] MS (ES) 307.3 [M+1] TABLE VIII

Structure

361

HH 307.3

[0751] Compounds 371 (listed in Table IX. below) were preparedsubstantially analogous to the following procedure II.

Procedure II

[0752] Preparation of 4-(2-Oxo-1-phenyl-ethyl)-piperazine-1-carboxylicacid tert-butyl ester (371). To DMSO (2.19 mL) in MeCl₂ (40 mL) at −78°C. was added (COCl)₂ (1.29 mL, X mmol) dropwise. The reaction mixturewas allowed to stir at −78° C. for 15 minutes and then4-(2-Hydroxy-1-phenyl-ethyl)piperazine-1-carboxylic acid tert-butylester (364) (3.78 g, 12.34 mmol) in MeCl₂ (8 mL) was added. The reactionmixture was allowed to stir at −78° C. for 1 h and then TEA (8.6 mL)amine added. The reaction mixture was allowed to stir at −78° C. foranother 3 h and then allowed to warm to room temperature and stirred for18 h. The reaction mixture is then quenched with sat. NH₄Cl (55 mL). Thedesired product is extracted into EtOAc (100 mL). The organic phase isdried over MgSO₄ and concentrated to dryness. The crude material waspurified by chromatography (silica gel 60 mesh, eluting with 30% EtOAcin hexanes) yielding 2.37 g (63%) pure product.

[0753] MS (ES) 303.4 [M-1] TABLE IX

Cmpd. # Structure

371

II

[0754] Compounds 401-463 (listed in Table X. below) were preparedsubstantially analogous to the following procedures for alkylation,sulfonylation, acylation, etc. of the respective 1° amines or acids.

Procedure H

[0755] Preparation of 2-(2-Chloro-phenyl)-2-piperazin-1-yl-acetamide(461). 4-[(2-Chloro-phenyl)-cyano-methyl]-piperazine-1-carboxylic acidtert-butyl ester (11) (1.0 g, 2.98 mmol) was dissolved in H₂SO₄ (5.0 mL)and allowed to stir at room temperature for 18 h. The reaction mixturewas cautiously poured over ice (50 mL) and made basic with 5N NaOH (50mL). The desired product was extracted into EtOAc (100 mL) The organicphase was concentrated to dryness yielding 0.64 g (85%) product.

[0756] MS (ES) 254.1 [M+1]

Procedure I

[0757] Preparation of 4-[Carbamoyl-(2-chloro-phenyl)-methyl]-piperazine-1-carboxylic acidtert-butyl ester (462). To2-(2-Chloro-phenyl)-2-piperazin-1-yl-acetamide (461) (0.64 g, 2.52 mmol)in a 1:1 mixture of THF/H₂O (5.0 mL) was added K₂CO₃ (0.77 g, 5.55mmol). The mixture was allowed stir for 15 min at room temperature.Boc-anhydride (0.60 g, 2.72 mmol) was then added and the reaction wasallowed to stir at room temperature for 18 h. The reaction mixture wasthen diluted with EtOAc (50 mL) and washed with sat. NaHCO₃ (50 mL) andbrine (50 mL). The crude material was purified by chromatography (silicagel 60 mesh, eluting with 5% MeOH in CHCl₃) yielding 0.50 g (56%) pureproduct.

[0758] MS (ES) 354.2 [M+1]

Procedure K

[0759] Preparation of 4-(Carboxy-o-tolyl-methyl)-piperazine-1-carboxylicacid tert-butyl ester (456). To4-(Ethoxycarbonyl-o-tolyl-methyl)-piperazine-1-carboxylic acidtert-butyl ester (152) (0.83 g, 2.27 mmol) in EtOH (10 mL) was addedNaOH (0.46 g, 11.38 mmol) and the mixture stirred at room temperaturefor 18 h. The reaction mixture was then concentrated to dryness. Theresulting residue was taken up in H₂O (100 mL) and acidified (pH=4-6)with 25% KHSO₄, and the desired acid was extracted into EtOAc (100 mL).The organic phase was washed with H₂O (100 mL) and brine (100 mL) andconcentrated to dryness yielding 0.66 g (86%) pure product.

[0760] MS (ES) 279.1 [M+1]

Procedure L

[0761] Preparation of4-(Diethylcarbamoyl-o-tolyl-methyl)-piperazine-1-carboxylic acidtert-butyl ester (457). To4-(Carboxy-o-tolyl-methyl)-piperazine-1-carboxylic acid tert-butyl ester(352) (0.654 g, 1.95 mmol) in DMF (5 mL) was added diethylcyanophosphonate (0.29 mL, 1.95 mmol), diethylamine (0.24 mL, 2.35 mmol)and TEA (0.32 mL, 2.35 mmol). The mixture was stirred at roomtemperature for 12 h and then diluted with EtOAc (50 mL). The reactionmixture was washed with sat. NaHCO₃ (50 mL), H₂O (50 mL) and brine (50mL). The organic phase was concentrated to dryness. The crude materialwas purified by chromatography (silica gel 60 mesh, eluting with 50%hexanes/50% EtOAc) yielding 0.60 g (79%) pure product.

[0762] MS (ES) 390.3 [M+1]

Procedure M

[0763] Preparation of Diethyl-(2-piperazin-1-yl-2-o-tolyl-ethyl)-amine(459). To LAH (0.08 g, 2.23 mmol) in THF (10 mL) was addedN,N-Diethyl-2-piperazin-1-yl-2-o-tolyl-acetamide (548) (0.22 g, 0.74mmol) in THF (10 mL). The reaction mixture was allowed to stir at refluxfor 8 h. Reaction was allowed to cool to room temperature and was thenquenched by the addition of H₂O (0.08 mL), 15% NaOH (0.25 mL) and H₂O(0.08 mL) again. The resulting aluminum salts were allowed to stir atroom temperature for 1 h and then removed by filtration. The filtratewas concentrated to dryness yielding 0.20 g (98%) product.

[0764] MS (ES) 190.1 [M+1]

Procedure N

[0765] Preparation of4-[1-(2-Chloro-phenyl)-2-diethylamino-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (449). To4[-2-Amino-1-(2-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (201) (2.15 g, 6.34 mmol) in DMF (15 mL) was addedK₂CO₃ (4.38 g , 31.71 rmuol) and ethyl bromide (2.07 g, 19.03 mmol). Thereaction mixture was allowed to stir at room temperature for 18 h. Thereaction mixture was diluted with EtOAc (100 mL) and washed with H₂O(100 mL) The organic phase was concentrated to dryness. The crudematerial was purified by chromatography (silica gel 60 mesh, elutingwith 5% MeOH in CHC₁ ₃) yielding 1.55 g (62%) pure product.

[0766] MS (ES) 396.2 [M+1]

Procedure O

[0767] Preparation of4-[2-Diethylamino-1-(2-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (404). To a solution of a4-[2-Amino-1-(2-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (204) (0.75 g, 2.01 mmol) in EtOH (50 mL) wasadded acetaldehyde (3.37 mL, 60.3 mmol) via RT distillation (warmingflask with hand). Halfway through the addition of the acetaldehyde,sodium cyanoborohydride (0.631 g, 10.05 mmol) was added. The reactionwas allowed to stir at room temperature for 18 h. The reaction mixturewas concentrated to dryness. The resulting residue was taken up in EtOAc(50 mL) and washed with sat. NaHCO₃ (50 ml) and brine (50 mL). Theorganic phase was concentrated to dryness yielding 0.860 g (99%)product.

[0768] MS (ES) 430.2 [M+1]

Procedure P

[0769] Preparation of4-[2-Diethylamino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (407). To4-[2-Amino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (207) (0.10 g, 0.309 mmol) in DMSO (8.0 mL) was addedK₂CO₃ (0.02 g, 0.111 mmol) and ethyl bromide (0.07 g, 0.618 mmol). Thereaction was allowed to stir at room temperature for 18 h. A catalyticamount of BU₄N⁺I⁻ was added and the reaction was allowed to stir another4 h. The reaction mixture was diluted with CHCl₃ (30 mL) and washed withH₂O (30 mL) and brine (30 mL). The organic phase was concentrated todryness. The crude material was purified by chromatography (silica gel60 mesh, eluting with a gradient of 100% EtOAc to 5% MeOH/5% TEA inEtOAc) yielding 0.06 g (50%) pure product.

[0770] MS (ES) 380.3 [M+1]

Procedure Q

[0771] Preparation of4-[2-Diethylamino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (413). To4-[2-Amino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (208) (0.10 g, 0.309 mmol) in acetic acid (3.0 mL) at0° C. was added NaBH₄ cautiously. The reaction was allowed to stir atroom temperature for 2 h. The reaction mixture was allowed to stir atreflux for 18 h. The reaction mixture was cooled to room temperature andchilled 35% NaOH (30 mL) was added. The desired product was extractedwith MeCl₂ (30 mL) and washed with H₂O (30 mL). The organic phase wasconcentrated to dryness yielding 0.11 g (94%) product.

[0772] MS (ES) 380.3 [M+1]

Procedure R

[0773] Preparation of4-[1-(2,4-Difluoro-phenyl)-2-methoxycarbonylamino-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (420). To4-[2-Amino-1-(2,4-difluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (209) (0.38 g, 1.13 mmol) in a 1:1 mixture of THF/H₂O(30 mL) was added NaOH (0.05 g, 1.24 mmol) and methyl chloroformate(0.11 g, 1.13 mmol ). The reaction was allowed to stir at roomtemperature for 2 h. The reaction mixture was then diluted with EtOAc(200 mL) and washed with H₂O (100 mL) and brine (100 mL). The organicphase was concentrated to dryness. The crude material was purified bychromatography (silica gel 60 mesh, eluting with 50% hexanes/50% EtOAc)yielding 0.23 g (50%) pure product.

[0774] MS (ES) 400.2 [M+1]

Procedure S

[0775] Preparation of4-[1-(4-Chloro-phenyl)-2-dimethylamino-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (403). To4-[2-Amino-1-(4-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (203) (0.18 g, 0.529 mmol) in MeCN (3.0 mL) at 0° C.was added formaldehyde(0.64 g, 21.18 mmol) and NaCNBH₃ (0.17 g, 2.65mmol). The reaction was allowed to warm to room temperature over 1 h.The reaction mixture was concnetrated to dryness. The resulting residuewas taken up in EtOAc (50 mL) and washed with sat. NaHCO₃ (50 mL) andH₂O (50 mL). The desired product was then extracted into 1N HCl (50 mL)and washed with EtOAc. This aqueous phase was made alkaline with 5N NaOH(25 mL) and the desired product was extracted into EtOAc (100 mL). Theorganic phase was concentrated to dryness yielding 0.10 g (53%) product.

[0776] MS (ES) 368.1 [M+1]

Procedure T

[0777] Preparation of4-[1-(2-Fluoro-phenyl)-2-methanesulfonylamino-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (408). To a solution of4-[2-Amino-1-(2fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (207) (0.71 g, 2.19 mmol) in THF (5 mL) at 0° C. wasadded diisopropylethylamine (0.42 mL, 2.42 mmol). The solution wasallowed to stir for 10 min. Methansulfonyl chloride (0.17 mL, 2.19 mmol)was then added and the solution was allowed to stir at room temperaturefor 18 h. The reaction mixture was diluted with EtOAc (50 mL) and washedwith brine (50 mL) and H₂O (50 mL). The organic phase was concentratedto dryness yielding 0.86 g (98%) product.

[0778] MS (ES) 402.2 [M+1]

Procedure U

[0779] Preparation of4-[2-(Ethyl-methanesulfonyl-amino)-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (409). To4-[1-(2-Fluoro-phenyl)-2-methanesulfonylamino-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (408) (1.43 g, 3.56 mmol) in THF (30 mL) was addedNaH (60% in oil) (0.16 g, 3.92 mmol) and the solution was allowed tostir for 1 h at room temperature. Iodoethane (0.31 mL, 3.92 mmol) wasthen added and the reaction was allowed to stir for 18 h. The reactionmixture was diluted with EtOAc (100 mL) and washed with H₂O (100 mL).The organic phase was concentrated to dryness. The crude material waspurified by chromatography (silica gel 60 mesh, eluting with 10% MeOH inCHCl₃) yielding 0.54 g (36%) pure product.

[0780] MS (ES) 430.2 [M+1]

Procedure V

[0781] Preparation of4-1-(2-Chloro-phenyl)-2-ethylamino-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (418). To4-[2-Amino-1-(2-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (201) (0.64 g, 1.68 mmol) in THF (5.0 mL) was added 1Mborane-THF complex in THF (15.02 mL, 5.03 mmol). The reaction wasallowed to stir at 60° C. for 1 h and then allowed to cool to roomtemperature. MeOH (6.0 mL) and diisopropylethylamine (3.0 mL) were thenadded followed by I₂ (0.84 g, 3.35 mmol) in THF (10 mL). The mixture wasallowed to stir at room temperature for 30 min. The mixture was thendiluted with EtOAc (50 mL) and washed with 1N sodium thiosulfate (50 mL)and H₂O (50 mL). The organic phase was concentrated to dryness yielding0.53 g (86%) pure product.

[0782] MS (ES) 368.2 [M+1]

Procedure W

[0783] Preparation of4-[2-Acetylamino-1-(2-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (416). To4-[2-Amino-1-(2-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (201) (0.75 g, 2.21 mmol) in pyridine (5 mL) was addedAc₂O (5 mL). The reaction was allowed to stir at 60° C. for 1 h and thenallowed to cool to room temperature. The reaction mixture was dilutedwith EtOAc (100 mL) and washed with sat. NaHCO₃ (100 mL)), H₂O (100 mL)and brine (100 mL). The organic phase was concentrated to drynessyielding 0.85 g (99%) product.

[0784] MS (ES) 388.2 [M+1]

Procedure CC

[0785] Preparation of4-[1-(2-Fluoro-phenyl)-2-methanesulfonylamino-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (408). To4-[2-Amino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (207) (1.45 g, 4.48 mmol) in MeCl₂ (10 mL) was addedmethanesulfonyl chloride (0.51 g, 4.48 mmol) and pyridine. The reactionwas allowed to stir at room temperature for 18 h. The reaction mixturewas then diluted with EtOAc (50 mL) and washed with H₂O (50 mL) andbrine (50 mL). The organic phase was concentrated to dryness yielding1.43 g (80%) product.

[0786] MS (ES) 402.2 [M+1]

Procedure DD

[0787] Preparation of4-[2-Ethoxycarbonylamino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (424). To4-[2-Amino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (207) (1.0 g, 3.09 mmol) was added ethyl chloroformate(15 mL) and the reaction mixture is allowed to reflux for 18 h. Thereaction mixture is then concentrated to dryness yielding 1.05 g(97%)product.

[0788] MS (ES). 352.2 [M+1]

Procedure EE

[0789] Preparation of4-[1-(2-Fluoro-phenyl)-2-methylamino-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (425). ToEthoxycarbonylamino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (207) (1.05 g, 3 mmol) in THF (10 mL) at −78° C.was added 1M borane in THF (4.5 mL). The reaction is stirred at −78° C.for 1 h and then was allowed to warm to room temperature (2 h). 5Naqueous sodium hydroxide was then added and the reaction was allowed tostir for 2 h. The reaction mixture was then diluted with EtOAc and thelayers are separated. The organic phase was dried with sodium sulfateand concentrated to dryness yielding 0.95 g (94%) product.

[0790] MS (ES) X [M+1]

Procedure FF

[0791] Preparation of4-[2-(Acetyl-methyl-amino)-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (426). To4-[1-(2-Fluoro-phenyl)-2-methylamino-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (425) (0.95 g, 2.81 mmol) in MeCl₂(10 mL) was added TEA(0.43 mL, 3.10 mmol). The solution was cooled to 0° C. and allowed tostir for 15 min. Acetyl chloride (0.20 mL, 2.81 mmol) was then added.The reaction was allowed to stir at 0° C. for 35 min and then at roomtemperature for 132 h. Additional triethylamine (0.39 mL, 2.81 mmol),and acetyl chloride (0.2 mL, 2.81 mmol) were added. The reaction mixturewas then diluted with 10% aq. sodium bisulfate (20 mL). The organiclayer was separated and the aqueous portion was extracted withdichloromethane (3×). The organics are combined, dried with sodiumsulfate and concentrated to dryness. The crude material was purified bychromatography (silica gel 60 mesh, eluting with 2% (2M NH₃ in MeOH) inMeCl₂) yielding 0.17 g (16%) pure product.

[0792] MS (ES) 380.3 [M+1]

Procedure JJ

[0793] Preparation of4-(2-Dipropylamino-1-phenyl-ethyl)-piperazine-1-carboxylic acidtert-butyl ester (427). To4-(2-Oxo-1-phenyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester(206) (0.47 g, 1.56 mmol) in dichloroethane (5 mL) was addeddiisopropylamine (0.21 mL, 1.56 mmol) and sodium triacetoxyborohydride(0.45 g, 2.15 mmol). The reaction was allowed to stir at roomtemperature for 18 h. The reaction mixture was then quenched with 5NNaOH (5.6 mL) and diluted with EtOAc. The organic phase was dried withMgSO₄ and concentrated to dryness. The crude material was purified bychromatography (silica gel 60 mesh, eluting with 100% EtoAc) yielding0.30 g (49%) pure product.

[0794] MS (ES) 390.4 [M+1]

Procedure KK

[0795] Preparation of4-[2-(2-Ethyl-butylamino)-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (438). To4-[2-Amino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester (207) (0.18 g, 0.56 mmol) in DMF (3 mL) was added1-bromo-2-ethyl-butane (0.083 mL, 0.59 mmol) and potassium carbonate(0.093 g, 0.68 mmol). The reaction was allowed to stir at roomtemperature for 18 h. The reaction mixture was then diluted with EtOAc(30 mL) and H₂O (30 mL). The organic phase was dried with sodium sulfateand concentrated to dryness. The crude material was purified bychromatography (silica gel 60 mesh, eluting with 3% (2M NH₃ in MeOH) inMeCl₂) yielding 0.13 g (59%) pure product.

[0796] MS (ES) 408.4 [M+1] TABLE X

Cmpd. # Structure

401

S 368.1 402

S 368.1 403

S 368.1 404

O 430.2 405

O 376.3 406

O N/A 407

N 380.3 408

T 402.2 409

U 430.2 410

N 398.2 411

N 398.2 412

N 448.4 413

N 380.3 414

N 396.3 415

FF 366.2 416

W 388.2 417

V 352.3 418

V 368.2 419

T 446.2 420

R 400.2 421

R 382.1 422

R* 396.2 w/ EtCl-Formate 423

R* 410.2 w/ iPrCl-Formate 424

DD 352.2 425

EE N/A 426

FF 380.3 427

JJ 390.4 428

JJ* 390.4 w/ iPrAmine 429

JJ* 374.3 w/ Pip 430

JJ* 376.3 w/ Morph 431

JJ* 360.4 w/ pyrr 432

FF 394.2 433

FF 408.2 434

FF 422.2 435

DD 410.3 436

DD 424.3 437

DD 438.4 438

KK 408.4 439

KK 420.4 440

FF 450.4 441

FF 462.4 442

N 430.2 “A” isomer #2 443

T 402.2 “A” isomer #2 444

O 429.2 445

O 429.2 446

O 396.3 447

O 392.3 448

O 376.3 449

O 396.3 450

O 392.3 451

T 418.2 452

W 366.2 “A” isomer #2 453

V 352.3 “A” isomer #2 454

T 430.3 “A” isomer #2 455

N 396.3 “A” isomer #1 456

K 279.1 457

L 390.3 458

X 290.3 459

M N/A 460

N 375.1 461

H 254.1 462

I 354.2 463

N 394.1

[0797] Compounds 491-492 (listed in Table XI. below) were preparedsubstantially analogous to the following procedure for the chiralsynthesis of the “A” piece from the appropriate commercially availablematerials.

Procedure LL

[0798] Preparation of 2-Diethylaanino-1-phenyl-ethanol (491). To(R)-phenylglycinol (0.50 g, 3.60 mmol) in THF (15 mL) was added Na₂CO₃(1.14 g, 10.80 mmol), tetrabutylammonium iodide (0.66 g, 1.80 mmol) andethyl iodide (0.60 g, 7.3 mmol). The reaction was allowed to reflux for24 h. The reaction mixture was allowed to cool to room temperature andthe precipitate was removed by filtration. The filtrate was concentratedto dryness. The resulting residue was taken up in EtOAc (50 mL) andwashed with H₂O (50 mL). The organic phase was dried with Na₂SO₄ andconcentrated to dryness. The crude material was purified bychromatography (silica gel 60 mesh, eluting with 5% TEA/5% MeOH inEtOAc) yielding 0.67 g (96%) pure product.

[0799] MS (ES) 194.2 [M+1] TABLE XI

491

LL 194.2 492

LL 194.2

[0800] Compounds 501-549 (listed in Table XII. below) were preparedsubstantially analogous to the following procedures for Boc-deprotectionof the appropriate “A” pieces or chiral synthesis.

Procedure MM

[0801] Preparation of Diethyl-(2-phenyl-2-piperazin-1-yl-ethyl)-amine(545). To 2-Diethylamino-1-phenyl-ethanol (491) (0.68 g, 3.50 mmol) inEt₂O (10 mL) was added TEA (1.40 mL, 10.50 mmol). The reaction mixturewas cooled to 0° C. and methanesulfonyl chloride (0.40 mL, 4.90 mmol)was added dropwise. The reaction mixture was allowed to stir at roomtemperature for 30 min. N-Boc-piperazine (1.30 g, 7.20 mmol) was thenadded and the reaction was stirred at room temperature for 18 h. Thereaction mixture was diluted with EtOAc (10 mL) and washed with H₂O (5mL). The organic phase was dried with Na₂SO₄ and concentrated todryness. The residue was purified by medium pressure chromatography(eluting with 5% TEA/5% MeOH in EtOAc) to afford the N-Boc protectedproduct in >98% EE (determined by chiral HPLC Chiralpak AD, Hexane-TFA0.05%, 1 mL/min, t=9.748). A solution of the N-Boc derivative (0.68 g,1.88 mmol) in 1N HCl/EtOAc (25 mL) was stirred at room temperature for18 h. The reaction mixture was concentrated to dryness and the resultingresidue was washed with Et₂O (100 mL) yielding 0.48 g (52%) product.

[0802] MS (ES) 262.2 [M+1]

Procedure X

[0803] Preparation of[2-(2,4-Difluoro-phenyl)-2-piperazin-1-yl-ethyl]-carbamic acid methylester (516). To4-[1-(2,4-Difluoro-phenyl)-2-methoxycarbonylamino-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (420) (0.225 g, 0.564 mmol) in MeCl₂ (2.0 mL) wasadded TFA (2.0 mL). The reaction was allowed to stir at room temperaturefor 1 h. The reaction mixture was concentrated to dryness. The resultingresidue was taken up in 1N HCl (30 mL) and washed with EtOAc (30 mL).The aqueous layer was made alkaline with 5N NaOH (10 mL) and the desiredproduct was extracted into EtOAc. The organic phase was concentrated todryness yielding 0.14 g (83%) pure product.

[0804] MS (ES) 300.2 [M+1] TABLE XII

501

X 268.1 502

X 268.1 503

X 268.1 504

X 330.2 505

X 276.3 506

X N/A 507

X 287.1 508

X 302.2 509

X 330.2 510

X 298.2 511

X 298.2 512

X 348.2 513

X 287.1 “A”isomer#2 514

X 296.3 “A”isomer#2 515

X 346.1 “A”isomer#2 516

X 300.2 517

X 282.1 518

X 296.1 519

X 310.1 520

X 280.1 521

X 290.3 522

X 290.3 523

X 274.2 524

X 276.2 525

X 260.2 526

X 294.2 527

X 308.2 528

X 322.2 529

X 310.3 530

X 324.3 531

X 328.3 532

X 350.4 533

X 362.4 534

X 330.1 “A”isomer#2 535

X 302.2 “A”isomer#2 536

X 330.1 537

X 330.1 538

X 296.3 539

X 292.3 540

X 276.3 541

X 296.3 542

X 292.3 543

X 318.1 544

MM 262.2 545

MM 262.2 546

X 330.2 “A”isomer190 1 547

X 275.1 548

X 290.2 549

X 294.1

[0805] Compounds 601-622 (listed in Table XIII. below) were preparedsubstantially analogous to the following procedures for amide couplingof the respective de-protected “A” pieces to the Boc-protected “B” piece(i.e 4-Cl-D-Phe).

Procedure Y

[0806] Preparation of(1-(4-Chloro-benzyl)-2-{4-[2-diethylamino-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-carbamricacid tert-butyl ester (608). ToDiethyl-[2-(2-fluoro-phenyl)-2-piperazin-1-yl-ethyl]-amine (513) (0.206g, 0.738 mmol) was added Boc-4-chloro-D-Phe (0.221 g, 0.738 mmol),1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.141 g,0.738 mmol), 1-Hydroxybenzotriazole hydrate (0.099 g, 0.738 mmol), DCM(5.0 mL) and 4-methylmorpholine (0.243 mL, 2.215 mmol). The reaction wasallowed to stir at room temperature for 4 h. The reaction mixture wasconcentrated to dryness. The resulting residue was taken up in EtOAc (30mL) and washed with sat. NaHCO₃ and brine. The crude material waspurified by chromatography (silica gel 60 mesh, eluting with 5% MeOH/5%TEA in EtOAc) yielding 0.41 g (99%) pure product.

[0807] MS 561.2 [M+1]

Procedure NN

[0808] Preparation of(1-(4-Chloro-benzyl)-2-{4-[1-(4-chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-carbamicacid tert-butyl ester (621). From[2-(4-Chloro-phenyl)-2-piperazin-1-yl-ethyll-diethyl-amine (538) 621 wassynthesized substantially analogous to Procedure Y and the diastereomerswere separated by chiral chromatography on a Chiralpak AD(4.6×250mm)column, eluting with 5% 3A alcohol, 95% heptane with 0.2% DMEA at 1mL/min. The second eluting isomer was labeled isomer 2.

[0809] MS (ES) 627.1 [M+1] TABLE XIII

601

Y 557.4 602

Y N/A 603

Y 611.2 604

Y 611.2 605

Y 561.3 606

Y 583.3 607

Y 611.4 608

Y 561.3 “A”isomer#2 609

Y 577.2 “A”isomer#2 610

Y 577.2 611

Y N/A 612

Y N/A 613

Y 627.1 “A”isomer#2 614

Y 611.1 “A”isomer#2 615

Y 583.1 “A”isomer#2 616

Y 611.1 617

Y 611.1 618

Y 557.3 619

Y 627.1 620

Y 573.4 621

NN 627.1 “A-B”isomer#2 622

NN 627.1 “A-B”isomer#1

[0810] Compounds 701-721 (listed in Table XIV. below) were preparedsubstantially analogous to Procedure X described above forBoc-deprotection of the respective Boc-protected coupled “A-B” pieces.TABLE XIV

701

X 457.4 702

X N/A 703

X 511.3 704

X 461.3 705

X 583.3 706

X 511.3 707

X 461.3 “A”isomer#2 708

X 477.2 “A”isomer#2 709

X 477.2 710

X N/A 711

X N/A 712

X 527.1 “A”isomer#2 713

X 511.1 “A”isomer#2 714

X 483.1 “A”isomer#2 715

X 511.1 716

X 511.1 717

X 457.3 718

X 527.1 719

X 473.3 720

X 527.1 “A”isomer#2 721

X 527.1 “A”isomer#1

[0811] Compounds 801-849 (listed in Table XV. below) were preparedsubstantially analogous to Procedure Y described above for amidecoupling of the respective de-protected “A-B” piece to the respective“C” piece (the synthesis of each non-commercially available “C” piece isdescribed in the section entitled “Preparation of Novel “C” and “B-C”Pieces” and other sections herein). TABLE XV

801

Y 716.4 Preparation C2 802

Y 716.5 Preparation C3 803

Y 716.3 “C”carboxylic acid is comm. Available 804

Y 716.3 “C”carboxylic acid is comm. Available 805

Y 770.5 Preparation C2 806

Y 770.5 Preparation C2 cis isomer 1 807

Y 770.5 Preparation C2 cis isomer 2 808

Y 720.4 Preparation C2 isomer 2 809

Y 742.4 Preparation C2 isomer 2 810

Y 770.4 Preparation C2 811

Y 720.4 “A”isomer#2 Preparation C2 isomer 2 812

Y, AA 616.2 “A”isomer#2 “C”carboxylic acid is comm. Available 813

Y, AA 648.6 “A”isomer#3 814

Y, AA 648.6 “A”isomer#4 815

Y 736.6 “A”isomer#2 Preparation C2 isomer 2 816

Y 650.3 “A”isomer#2 Preparation C5 isomer 2 817

Y 750.3 “A”isomer#2 Preparation C3 818

Y 750.3 “A”isomer#2 Preparation C3 819

Y 734.3 “A”isomer#2, “C”isomer#2 Preparation C3 820

Y 634.3 “A”isomer#2 Preparation C6 isomer 2 821

Y 734.4 “A”isomer#2, “C”isomer#1 Preparation C3 822

Y 720.3 Preparation C9 823

Y 720.3 Preparation C15 824

Y 750.6 “C”isomer#1 Preparation C9 825

Y 750.6 “C”isomer#2 Preparation C10 826

Y 790.5 Preparation C2 isomer 2 827

Y 802.4 Preparation C2 isomer 2 828

Y 786.1 “A”isomer#2 Preparation C2 isomer 2 829

Y 800.1 “A”isomer#2 Preparation C3 isomer 2 830

Y 684.1 “A”isomer#2 Preparation C6 isomer 2 831

Y 784.1 “A”isomer#2 Preparation C3 isomer 2 832

Y 742.1 “A”isomer#2 Preparation C2 isomer 2 833

Y 656.1 “A”isomer#2 Preparation C6 isomer 834

see Preparation BC3-C 688.1 Preparation BC3 835

see Preparation BC3-C 722.1 Preparation BC3 836

Y 770.3 “A”isomer#2 Preparation C2 isomer 2 837

Y 736.3 Preparation C2 838

Y 770.3 Preparation C2 839

Y 770.3 Preparation C2 840

Y, AA 632.2 “C”carboxylic acid is comm. Available 841

Y 716.4 Preparation C2 842

Y 736.3 Preparation C2 isomer 1 843

Y 732.2 Preparation C2 isomer 2 844

Y 750.5 Preparation C14 845

Y 750.4 “A”isomer#2, “C”isomer#2 Preparation C3 846

Y 736.4 “A”isomer#1 “C”carboxylic acid is comm. Available 847

Y 736.4 “A”isomer#2 “C”carboxylic acid is comm. Available 848

Y Preparation C2 isomer 2 849

Y Preparation C2 isomer 1

[0812] Compounds 901-902 (listed in Table XVI. below) were preparedsubstantially analogous to the following procedure for amide coupling ofthe respective de-protected “A” pieces to the respective pre-coupled“B-C” piece (the synthesis of each non-commercially available “B-C”piece is described in the section entitled “Preparation of Novel “C” and“B-C” Pieces” and other section herein).

Procedure Z

[0813] Preparation of3-(4-Chloro-benzyl)-2-{4-[1-(2,4-difluoro-phenyl)-2-methoxycarbonylamino-ethyl]-piperazin-1-yl}-2-oxo-ethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (917). To[2-(2,4-Difluoro-phenyl)-2-piperazin-1-yl-ethyl]-carbamic acid methylester (516) (0.14 g, 0.47 mmol),3-[1-Carboxy-2-(4-chloro-phenyl)-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (0.22 g, 0.47 mmol) andO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.178 g, 0.47 mmol) was added MeCl₂ (1.0 mL) andDMF (0.2 mL) followed by DIPEA (0.82 mL, 4.7 mmol). The reaction wasallowed to stir at room temperature for 4 h. The reaction mixture wasthen concentrated to dryness. The resulting residue was taken up inEtOAc (30 mL) and washed with sat. NaHCO₃ (30 mL) and brine (30 mL). Theorganic phase was concentrated to dryness. The crude material waspurified by chromatography (silica gel 60 mesh, eluting with a gradientof 100% EtOAc to 5% TEA/5% MeOH in EtOAc) yielding 0.34 g (98%) pureproduct.

[0814] MS (ES) 740.2 [M+1] TABLE XVI Prepared analogous Compound to MSES Additional # Structure Procedure (M + 1) info 951

Z 734.7 952

Z 720.7

[0815] The TFA or HCl salts of compounds 1001-1105 (listed in Table XVIIbelow) were prepared substantially analogous to the following procedurefor deprotection and purification of their respective Boc-protected“A-B-C” precursor. HPLC purification as described may allow forresolution of a racemic compound.

Procedure AA

[0816] Preparation of5[2-(4-{3-(4-Chloro-phenyl)-2-[(1,2,3,4-tetrahydro-isoquinoline-3-carbonyl)-amino]-propionyl}-piperazin-1-yl)-2-(2,4-difluoro-phenyl)-ethyl]-carbamricacid methyl ester (1035). To3-(1-(4-Chloro-benzyl)-2-{4-[1-(2,4-difluoro-phenyl)-2-methoxycarbonylamino-ethyl]-piperazin-1-yl}-2-oxo-ethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (917) (0.340 g, 0.461 Tmnol) in MeCl₂ (1.0 mL) wasadded TFA (1.0 mL) and the reaction was allowed to stir at roomtemperature for 1 h. The reaction mixture was then concentrated todryness. The product was isolated as the TFA salt by trituration withEt₂O and filtration. The compound was further purified by HPLC (WatersSymmetry column—Part # WAT066245, flow rate: 20 mL/min, gradient: 10%MeCN in H₂O (with TFA modifier) to 40% MeCN in H₂O). 0.320 g (80%) pureTFA salt of the desired product was isolated.

[0817] MS (ES) 640.2 [M+1]. The TFA salt can be converted to the HClsalt by using an HCl modifier/buffer during the HPLC run, or bydissolving the TFA salt in 1N HCl and lyophilizing overnight or asappropriate. TABLE XVII Prepared analogous MS ES Additional Cmpd. #Structure to Procedure (M + 1) Info. 1001

AA 608.1 1002

AA 608.1 1003

AA 608.1 1004

AA 660.3 1005

AA 660.3 isomer #1 (of 2 - HPLC) 1006

AA 660.3 isomer #2 (of 2 - HPLC) 1007

AA 616.4 1008

AA 616.4 1009

AA 616.4 1010

AA 616.4 1011

AA 616.4 1012

AA 670.2 isomer #2 - UNK (of 4 - HPLC) 1013

AA 670.2 isomer #4 - UNK (of 4 - HPLC) 1014

AA 616.4 isomer #1 (of 4 - HPLC) 1015

AA 616.4 isomer #2 (of 4 - HPLC) 1016

AA 670.2 isomer #1 (of 2 - HPLC) C domain isomer #2 1017

AA 670.2 isomer #2 (of 2 - HPLC) C domain isomer #1 1018

AA 670.2 isomer #1 (of 2 - HPLC) C domain isomer #2 1019

AA 670.2 isomer #2 (of 2 - HPLC) C domain isomer #2 1020

AA 620.3 1021

AA 640.4 1022

AA 620.4 C domain isomer #2 1023

AA 642.4 C domain isomer #2 1024

AA 670.3 1025

AA 606.4 1026

AA 628.1 1027

AA 656.4 1028

AA 638.2 1029

AA 638.2 1030

AA 688.2 1031

AA 620.3 “A”isomer #2 C domain isomer #2 1032

AA 620.4 “A”isomer #2 1033

AA 636.3 “A”isomer #2 1034

AA 686.2 “A”isomer #2 1035

AA 640.2 1036

AA 616.4 isomer #3 (of 4 - HPLC) 1037

AA 616.4 isomer #4 (of 4 - HPLC) 1038

AA 636.2 “A”isomer #2 C domain isomer #2 1039

AA 650.3 “A”isomer #2 1040

AA 650.3 “A”isomer #2 1041

AA 635.1 “A”isomer #2, “C”isomer #1 1042

AA 634.1 “A”isomer #2, “C”isomer #1 1043

AA 622.1 1044

AA 636.2 1045

AA 650.2 1046

AA 620.2 1047

AA 630.3 1048

AA 630.3 1049

AA 614.2 1050

AA 616.2 1051

AA 600.2 1052

AA 620.3 1053

AA 620.3 1054

AA 650.3 “C”isomer #1 1055

AA 651.3 “C”isomer #2 1056

AA 634.2 1057

AA 648.2 1058

AA 662.2 1059

AA 650.3 1060

AA 664.4 1061

AA 678.4 1062

AA 690.5 C domain isomer #2 1063

AA 702.3 C domain isomer #2 1064

AA 686.1 “A”isomer #2 C domain isomer #2 1065

AA 700.1 “A”isomer #2 1066

AA 684.1 “A”isomer #2 1067

AA 642.1 “A”isomer #2 C domain isomer #2 1068

AA 588.1 1069

AA 622.1 1070

AA 634.3 “A”isomer #2, “C”isomer #1 1071

AA 634.3 “A”isomer #2, “C”isomer #2 1072

AA 670.3 “A”isomer #2 1073

AA 670.3 “A”isomer #2 1074

AA 670.2 1075

AA 636.1 1076

AA 636.0 1077

AA 670.2 1078

AA 670.2 1079

AA 670.2 1080

AA 632.4 1081

AA 616.4 1082

AA 616.4 1083

AA 636.0 “A”isomer #1 C domain isomer #1 1084

AA 636.0 “A”isomer #2 C domain isomer #1 1085

AA 636.0 “A”isomer #1 1086

AA 636.0 “A”isomer #2 C domain isomer #2 1087

AA 632.3 1088

AA 632.3 C domain isomer #2 1089

AA 650.3 “C”isomer #1 1090

AA 650.3 “C”isomer #2 1091

AA 658.2 1092

AA 620.3 1093

AA 602.3 1094

AA 602.3 1095

AA 670.3 “A”isomer #2 1096

AA 636.3 “A”isomer #1 1097

AA 616.4 1098

AA 650.3 “A”isomer #2, “C”isomer #2 1099

AA 636.3 “A-B”isomer #1 1100

AA 636.3 “A-B”isomer #2 1101

AA 616.3 1102

AA 602.0 C domain isomer #2 1103

AA 602.0 C domain isomer #1 1104

AA 634.4 1105

AA 620.5

Preparation of Novel C-Domain Pieces

[0818] Heck Coupling

Preparation PP1

[0819] Synthesis of Compound (2a) by a Heck Coupling of2-bromobenzaldehyde (1a) with methyl acrylate (Pd(OAc)₂/PPh₃ as thecatalyst):

[0820] A mixture of 2-bromobenzaldehye (1a) (24.5 g, 132 mmol), methylacrylate (17.9 mL, 199 mmol), Pd(OAc)₂ (590 mg, 2.65 mmol, 2 mol %),PPh₃ (1.39 g, 5.30 mmol, 4 mol %) and Et₃N (46 mL, 331 mmol) was stirredat 80° C. for 15 h. Large amount of yellow solid was formed after thereaction was done. The mixture was cooled to rt, concentrated, and mixedwith H₂O (200 mL). The organic solid was collected by filtration, andthen applied to a plug of silica gel (25 g) (EtOAc/hexane 1:1) to give adark yellow solid. The solid was purified by crystallization (100 mLEtOAc bottom layer, 120 mL hexane top layer) to provide 17.57 g (70%)(100% pure by NMR) of the first crop and 5.23 g (21%) (95% by NMR) ofthe second crop of 2a.

Preparation PP2

[0821] Synthesis of Compound (2a) by a Heck Coupling of2-bromobenzaldehyde (1a) with Methyl Acrylate (R═H)(Pd(OAc)₂/P(O-Tolyl)₃ as the catalyst):

[0822] The compound 1a (9.998 g, 54.04 mmol) was dissolved in toluene(20 mL) at r.t. Methylacrylate (5.996 g, 69.65 mmol, 1.29 eq.), NEt₃ (15mL), Pd(OAc)₂ and P(O-Tolyl)₃ were successively added and the mixturewas stirred under reflux. After 2 hours, the reaction mixture wasallowed to cool to RT. Then the precipitated yellow catalyst was removedby filtration. The catalyst was rinsed with toluene (2×10 mL) and thefiltrates were concentrated to dryness under reduced pressure. Theresidual oil was dried under vacuum over the weekend to give a crudesolid (11.449 g). The solid was taken-up with isopropanol (25 mL) andstirred overnight at RT. Then, the precipitate was filtered and rinsedwith isopropanol (5 mL). The wet cake (8.240 g) was dried overnight atRT affording the highly pure 2-carboxaldehyde-methyl-cinnamate with 74%yield (7.627 g, 40.1 mmol).

Preparation PP3

[0823] Heck Coupling of 1b and methyl acrylate to form 2b (R=5-OMe):

[0824] A mixture of 2-bromo-5-methoxybenzaldehyde (1b) (4.5 g, 20.9mmol, Aldrich), methyl acrylate (2.7 g, 1.5 eq, 2.83 mnL), Et₃N (7.4 g,3.5 eq, 10.2 mL), Pd(OAc)₂ (93 mg, 0.02 eq), and P(O-Tol)₃ was stirredand heated to 80° C. over 2-3 days. The reaction mixture was cooled tor.t., partitioned between EtOAc (50 mL) and brine (50 mL). The aqueouswas extracted with EtOAc (2×50 mL). The combined organic was washed withbrine (1×50 mL), dried over MgSO₄, filtered, concentrated to yield ayellow brown oil (5.01 g, 109%). This crude oil was purified in a hotsolvent Hex/EtOAc (80 mL/ 15 mL) to yield 2b as a pale yellow solid (3.5g, 76%).

Preparation PP4

[0825] Heck Coupling of 1c and Methyl Acrylate to Form 2c (R=4,5-OMe):

[0826] To a solution of 1c (906 mg, 3.70 mmol) in toluene (2 mL) wasadded Pd(OAc)₂ (17 mg, 0.074 mmol, 2 mol %), P(O-Tolyl)₃ (45 mg, 0.148mmol, 4 mol %), methyl acrylate (0.5 mL, 5.55 mmol) and Et₃N (1.5 mL,11.1 nmol). The mixture was stirred at 80 OC for 21 h, cooled to rt, andmixed with H₂O (40 mL). The organic compounds were extracted with EtOAc(50 mL), washed with brine (40 mL), dried (Na₂SO₄), and concentrated.The residue was purified by flash chromatography to provide 466 mg (47%)of recovered 1c followed by 450 mg (49%) of 2c (4,5-Ome).

Preparation PP5

[0827] Heck Coupling of 1d and Methyl Acrylate to Form 2d (R=5-NO₂):

[0828] The procedure is same as that of 2c, yielding 82% of 2d afterpurification.

Preparation PP6

[0829] Reductive Amination

[0830] Reductive amination of (2a) with benzyl amine to form isoindoline(10a). To a solution of 2a (11.27 g, 59.2 mmol) in ClCH₂CH₂Cl (60 mL)was added BnNH₂ (6.47 mL, 59.2 mmol), followed by HOAC (5.1 mL, 89mmol). The mixture was stirred at rt for 1 h. NaCNBH₃ (5.58 g, 88.8mmol) and MeOH (30 mL) were then added to the above solution. Theresulting mixture was stirred at rt for another 2 h and quenched withsat. NaHCO₃ solution (150 mL). The mixture was extracted with EtOAc(2×100 mL) and the combined organic layers were washed with brine (150mL), dried (Na₂SO₄), and concentrated to provide 15.3 g of crude productof 10a which was carried out for the next hydrogenolysis reaction.

Preparation PP7

[0831]

[0832] One-pot process from 2-carboxaldehyde-methyl-cinnamate to targetcyclized isoindoline product using NaBH₃CN.2-carboxaldehyde-methyl-cinnamate 2a (3.254 g, 17.1 mmol) was dissolvedin a 1:1 MeOH: PhCH₃ mixture (20 mL) at RT. R-(+)-phenethylamine (2.073g, 17.1 mmol) was added and the solution was heated under reflux for 2hours. HPLC in process control indicated that the imine formation wascompleted. Then, AcOH (2.055 g, 34.2 mmol) and NaBH₃CN (2.15 g, 34.2mmol) were successively added at RT, the reaction mixture being cooledwith a water-bath. The reaction mixture was post-agitated overnight.Water (10 mL), MeOH (20 mL) and 37% HCl (2.8 mL) were successively addedand the organic layer was extracted. The aqueous layer was washed withPhCH₃ (10 mL). Then, the aqueous layer was made basic with 5N NaOH (20mL) and MeOH was concentrated to partly remove MeOH. Extraction withEtOAc (2×25 mL) was performed. The combined organic layers were driedover MgSO4, filtered and rinsed with EtOAc (10 mL). The filtrates wereconcentrated under reduced pressure and the residual oil was dried undervacuum overnight at RT to afford the target cyclized isoindoline product10b with 92% yield (4.642 g, 15.7 mmol). HPLC % area indicated that the2 diastereomers were produced in a 55:45 ratio. ¹H NMR confirmed thisresult by integration of the methyl group of the phenethyl substituert.

[0833] Note: The Heck or Heck-type coupling was performed in toluenewith a slight excess of methylacrylate which was removed by distillationbefore the MeOH and the R-(+)-phenethylamine addition.

Preparation PP8

[0834]

[0835] Reductive amination of (2a) with t-butyl carbamate to form (11a):To a solution of aldehyde 2a (238 mg, 1.25 mmol) in CH₃CN (8 mL) wasadded t-butyl carbamate (439 mg, 3.75 mmol), followed by triethylsilane(0.6 mL, 3.75 mmol) and TFA (0.19 mL, 2.5 mmol). The mixture was stirredat rt overnight, quenched with sat. NaHCO₃ solution (20 mL) andextracted with EtOAc (2×30 mL). The combined organic layers were washedwith brine (30 mL), dried (Na₂SO₄) and concentrated. The residue waspurified by flash chromatography (hexane/EtOAc 3:1) to provide 317 mg(87%) of 11a.

Preparation PP9

[0836]

[0837] Reductive amination of 2b with t-butyl carbamate to form 11b: Amixture of aldehyde 2b (600 mg, 2.72 mmol) Et₃SiH (955 mg, 3 eq, 1.31mL), TFA (620 mg, 2 eq, 420 uL), t-butyl carbamate (980 mg, 3 eq) inacetonitrile (15 mL) was stirred at room temperature over 2 days.Removed the solvent on a Rotary evaporator and purified the cruderesidue on a flash column (100 g SiO₂, 7:1→6:1 Hex/EtOAc). Collected 307mg good desired product 11b (35%); 195 mg product contaminated withaldehyde SM (22%).

Preparation PP10

[0838]

[0839] Reductive amination of (2c) with t-butyl carbamate to form (11c):To a solution of aldehyde 2c (411 mg, 1.64 mmol) in CH₃CN (10 mL) wasadded t-butyl carbamate (580 mg, 4.93 mmol), followed by triethylsilane(0.8 mL, 4.93 mmol) and TFA (0.25 mL, 3.28 mmol). The mixture wasstirred at rt overnight, quenched with sat. NaHCO₃ solution (30 mL) andextracted with EtOAc (2×30 mL). The combined organic layers were washedwith brine (30 mL), dried (Na₂SO₄) and concentrated. The residue waspurified by flash chromatography (hexane/EtOAc 3:1, hexane/EtOAc 1:1) toprovide 535 mg (93%) of 11c.

Preparation PP11

[0840]

[0841] To a solution of 2d (1.02 g, 4.34 mg) in CH₂Cl₂/CH₃CN (1:1 24 mL)was added BocNH₂ (1.5 g, 13.02 mmol), Et₃SiH (2.1 mL, 13.02 mmol), andTFA (0.67 mL, 8,67 mmol). The mixture was stirred at rt for 7 h. Aprecipitate was formed during the reaction. The reaction mixture wasquenched with sat. NaHCO₃ solution (30 muL), and diluted with CH₂Cl₂ (40mL). The organic layer was washed with brine (30 mL), dried (Na₂SO₄),and concentrated. The residue was purified by flash chromatography(hexane/EtOAc 3:1, then CH₂Cl₂/EtOAc 10:1) to provide 2.08 g yellowsolid which still containing BocNH₂. The product is not the desiredBoc-carbamate 14c. LC-MS result showed that the product is the Schiffbase intermediate.

[0842] To the above product (420 mg) in CH₂Cl₂ (10 mL) was added Et₃SiH(1 mL) and TFA (6.4 mL). The mixture was stirred at rt for 1 h and smallamount of sample was taken for NMR. NMR analysis demonstrated that thestarting material was consumed and the product was 14c. TFA (0.7 mL) wasthen added to the above mixture and the resultant solution was stirredat rt for another 5 h and concentrated. The residue was dissolved inEtOAc (20 mL) and washed with H₂O (10 mL). The aqueous layer wasbasified with sat. NaHCO₃ (30 mL) and the organic compounds wereextracted with CH₂Cl₂ (2×25 mL). The combined organic layers were washedwith brine (20 mL), dried (Na₂SO₄) and concentrated to provide 218 mg ofthe cyclized compound 14c.

Preparation PP12

[0843]

[0844] Condensation of 2a with α-Methylbenzylamine to Form Imine 9.2-carboxaldehyde-methyl-cinnamate 2a (0.897 g, 4.72 mmol) was dissolvedin MeOH (10 mL) at RT. R-(+)-phenethylamine (0.577 g, 4.76 mmol) wasadded and the solution was heated under reflux for 2 hours. HPLC inprocess control indicated that the imine formation was completed. Thesolvent was stripped on a rotary evaporator and the resulting oil wasdried at RT under vacuum overnight. The Schiff base 9 was obtainedalmost quantitatively (1.412 g, 4.81 mmol).

Preparation PP13

[0845] Michael Addition:

[0846] The compound of a-Methyl benzylamine was applied as theauxiliary. As shown above, the one-pot reaction of aldehyde 2a andα-Methyl benzylamine gave 90% of 10b with a ratio of 1.2:1.

[0847] Step-wise reduction, amination, and cyclization: Condensation ofaldehyde 2a with α-methylbenzylamine in acetonitrile, methanol,methanol/toluene (1:1) or toluene afforded imine 9 in excellent yield.Reduction of the imine was initially carried out at RT withNaCNBH₃/HOAc. As a result, a poor ee ratio (1.2:1) was obtained,similarly to the previous described one-pot procedure. But when thereaction was carried out with NaBH₄/TFA at RT, the ratio was elevated to2:1. By lowering the reaction temperature to −78° C., the ratio wasincreased to 5 to 6:1.

Preparation PP14

[0848] Cyclization of t-Butyl carbamate (11a):

[0849] The N-Boc isoindoline methyl ester 12 was originally synthesizedfrom 11a via deprotection of Boc with TFA, followed by basic workup, andprotection with a Boc group. This procedure has been greatly improved bya one-step procedure.

Preparation PP15

[0850]

[0851] In a 3 L 3-neck round bottom flask equipped with a nitrogeninlet, thermocouple and mechanical stirrer, a solution of 160 g (1.15moles) of K₂CO₃ in 180 mL of water was stirred at rt. Solid BOCanhydride 120 g (0.55 moles) was added in one portion forming asemi-solution. To the reaction mixture, a solution of the crude aminoester starting material, 87 g (0.46 moles) in 120 mL of THF was addedslowly at such a rate to keep the internal temperature below 35° C. Amild effervescence was observed. The reaction mixture was stirred for 18hours at rt. Analysis of a reaction aliquot via NMR (DMSO₆) indicatesthe desired product. The reaction was diluted with brine and the productextracted with EtOAc. The organic layer was dried over Na₂SO₄, filtered,and concentrated to yield a dark oil, 150.1 g, >100% yield. The crudematerial was taken on to the next step.

Preparation PP16

[0852]

[0853] In a 3-L 3-neck round bottom flask equipped with a mechanicalstirrer, thermocouple, and reflux condenser, a solution of 150 g(approx. 0.46 moles) of crude N-BOC ester starting material in 750 mL ofmethanol was stirred at rt. To the solution, 750 mL of water was addedand the cloudy mixture was stirred vigorously. Solid LiOH 25 g (1.03moles) was added in small portions at such a rate to maintain theinternal temperature below 45° C. Upon completion of addition, thereaction was stirred overnight at rt becoming a dark green color. After18 hours the reaction was concentrated to yield a thick semisolid. Thecrude product was dissolved in EtOAc and washed with 1 N HCl quickly,followed by two brine washes. The organic layer was dried with Na₂SO₄,filtered and concentrated to yield 81 g of a dark green solid. Theaqueous layers were combined and back extracted with methylene chloride,dried over Na₂SO₄, filtered, and concentrated to yield 6 g of a darkgreen solid. Both solids were combined to yield 87 g of desired productconfirmed via NMR (DMSO₆).

Preparation PP17

[0854]

[0855] Synthesis of 14b: Dissolved the N-boc compound 11b (200 mg, 0.62mmol) in CH₂Cl₂ (1.0 mL). Cooled the clear light yellow solution to 0°C. Added slowly TFA (˜710 mg, 10 eq, ˜500 □L) via a syringe. Removed thecooling bath and stirred the clear light brown solution at RT overnight.TLC (3:1 Hex/EtOAc, UV) confirmed a complete reaction. Removed the TFAon a rotavapor. Added EtOAc and concentrated again (twice). The cruderesidue was partitioned between EtOAc (10-15 mL) and a sat. NaHCO₃(10-15 mL). The aqueous was extracted with EtOAc (2×10 mL). The combinedorganic was dried over MgSO₄, filtered, and concentrated to yield alight brown wet solid (212 mg, 138 %). NMR (CD₃OD) confirmed the desiredisoindoline 14b. This crude isoindoline was used in the next protectionstep without purification.

Preparation PP18

[0856] Synthesis of 12b: To a mixture of the isoindoline 14b (190 mg,0.859 mmol), K₂CO₃ (189 mg, 1.5 eq) in a solvent 1:1 THF/H₂O (1.0 mL) atRT was added BOC₂O (210 mg, 1.1 eq). The reaction mixture was stirred atRT overnight. TLC (3:1 Hex/EtOAc, UV) confirmed a complete reaction.Diluted the mixture with EtOAc (15 mL), and washed with H₂O (1×20 mL).The aqueous was extracted with EtOAc (1×20 mL). The combined organic waswashed with brine (1×20 mL), dried over MgSO₄, filtered, concentrated toyield a clear brown oil (340 mg, 123%). This crude oil was purified on aprep TLC plate (2×1,000 micron, solvent 2:1.5:0.5 CHCl₃/Hex/EtOAc) toyield 12b a clear yellow oil (190 mg, 69%). ¹H and ¹³C NMR (CDCl₃) wereobtained.

Procedure PP19

[0857] Synthesis of 12d (5-NO₂) by Boc-protection. The compound wasprepared by following the same procedure as described for 12b.

Preparation PP20

[0858]

[0859] The imine 9 (1.412 g, 4.81 mmol) was dissolved in anhydrous THF(10 mL) at RT and TFA (5 mL) was added. The black solution was thencooled to −78° C. (dry ice bath) and NaBH₄ (0.893 g, 23.6 mmol, 5 eq)was added in 2 portions over 5 minutes. Then, the reaction mixture waspost-agitated at −78° C. for 3 hours and allowed to gently warm at RTovernight. Water (20 mL), cyclohexane (10 mL) and EtOH (20 mL) weresuccessively added and the organic layer was extracted and discarded.The aqueous layer was made basic with 5N NaOH (20 mL) and extrated twotimes with a 2:1 EtOAC/PhCH₃ mixture (30 mL). The combined organiclayers were dried over MgSO4, filtered and rinsed with EtOAc (10 mL).The filtrates were concentrated under reduced pressure and the residualoil was dried under vacuum overnight at RT to afford the target cyclizedisoindoline product 10b (1.273 g, 4.31 mmol) with 91.4% yield. HPLC %area indicated that the 2 diastereomers were produced in a 84:16 ratio(de 68%). ¹H NMR confirmed this result by integration of the methylgroup of the phenethyl substituent.

Preparation PP20

[0860]

[0861] N-Boc methyl ester 11a (36.3 g, 0.125 mol) was dissolved in THF(250 mL), and the solution was cooled to about 0° C. A solution ofpotassium bis(trimethylsilyl) amide (1.24 g, 0.05 mol. Eq.) was addedslowly via a syringe under nitrogen atmosphere. The temperature wasraised about 8 degrees during the addition. The cooling bath was removedand the solution was stirred at r.t. for 30-45 min. The clear brownsolution was poured into a separation funnel containing about 100 mL ofa saturated NH₄Cl. The layers were separated. The aqueous layer wasextracted with EtOAc (2×50 mL). The combined organic was washed withbrine (1×100 mL), dried over Na₂SO₄, filtered, concentrated on a Rotaryevaporator to a clear yellow oil (37.3 g). This crude oil was purifiedon a flash column (600 g SiO₂), with a gradient solvent 6:1 Hex/EtOAc(2.1 L), 5:1 Hex/EtOAc (1.2 L), 4:1 Hex/EtOAc (1.5 L) to yield 12a as aclean yellow oil (34.5 g, 95%).

Preparation PP21

[0862]

[0863] To a solution of 11c (535 mg, 1.52 mmol) in THF (10 mL) was addedKHMDS (0.5 M in toluene, 0.1 mL, 0.05 mmol, 2 mol %). The mixture wasstirred at r.t. for 20 min, quenched with sat. NH₄Cl solution (20 mL),and diluted with EtOAc (20 mL). The organic layer was separated, washedwith brine (20 mL), dried (Na₂SO₄) and concentrated. The residue wasfiltered through a plug of silica gel (EtOAc/CH₂Cl₂ 1:10) to give 530 mg(99%) of 12c as an off white soild.

Preparation PP22

[0864] Deprotections:

[0865] Hydrogenolysis of 10a (R=Bn) to Form (14a): To a solution ofcrude 10a (15.3 g, 54.4 wool) in MeOH (100 mL) was added Pd(OH)₂/C(Pearlmants catalyst, 1.02 g, 6 mol %) in a par-shaker bottle. Thesuspension was shaken under 30 psi H₂ pressure overnight in thepar-shaker, and filtered through a plug of celite. The filtrate wasconcentrated to provide 10.1 g of crude 14a as brown oil. (The procedureis same for the methyl benzylamine isoindoline substrate 10b)

Preparation PP23

[0866]

[0867] In a typical reaction a mixture of the isoindoline ester 12a (92mg, a.316 mmol) in 1:1 MeOH/H₂O (2 ml) was treated with LiOH (15 mg, 2eq) at RT overnight. Diluted the mixture with CH₂Cl₂ (5 ml) and water (5ml). Adjusted the pH of the reaction mixture to 1-3 with a 10% NaHSO₄solution. Separated the layers. The aqueous was extracted with CH₂Cl₂(1×10 ml). The combined organic was dried over Na₂SO₄, filtered,concentrated to yield 16a as a pale yellow foam (76 mg, 87%). NMR(CDCl₃) showed a clean desired acid product.

[0868] It is noted that he reaction time must be more than 6 hours. Thecrude foam can be purified by slurry in warm hexane and then filter toyield a tan solid. Hydrolysis using KOH (2-5 eq) in 1:1 MeOH/H₂Oovernight would give the same result.

Preparation PP24

[0869] Resolution:

[0870] Purification of Partially Resolved Isoindolinecaboxylic acidmethyl ester: A solution of the crude material (97.62 g)isoindolinecaboxylic acid methyl ester in CH₂Cl₂ (350 mL) was extractedwith 1M HCl (400 mL, 200 mL). The combined aqueous portions were washedwith CH₂Cl₂ (4×250 mL) and then made basic with K₂CO₃ solution (85 g in150 mL of water). The mixture was extracted with CH₂Cl₂ (6×100 mL) andthe combined organic extracts were dried (Na₂SO₄) and concentrated togive partially resolved Isoindolinecaboxylic acid methyl ester as an oil(33.2 g). 60% ee by chiral CE.

Preparation PP25

[0871]

[0872] Resolution of Partially Resolved Isoindolinecaboxylic acid methylester: A solution of partially resolved isoindoline-caboxylic acidmethyl ester (33.24 g, 0.174 mol) in EtOH (130 mL) was treated slowlywith a solution of dibenzoyl-L-tartaric acid (56.06 g, 0.156 mol) inEtOH (200 mL). The solution was seeded with seeded with product andstirred at RT for 4 hours. Pure product was collected by filtration,washed with EtOH (30 mL) and dried to off-white crystals (60.49 g).96.5% ee by chiral CE.

Preparation PP26

[0873]

[0874] Resolution of N-BOC Isoindolinecaboxylic acid: A solution/slurryof racemic N-BOC Isoindolinecaboxylic acid (114.5 g, 0.413 mol) in EtOAc(1000 mL) was treated slowly with triethylamine (28.8 mL, 0.206 mol),followed by (S)-(−)-□-methylbenzylamine. The solution was seeded withproduct and stirred at RT overnight. The product was collected byfiltration, washed with EtOAc (200 mL) and dried to a white powder(62.98 g). 97.6% ee by chiral CE.

Asymmetric Hydrogenation Routes

[0875] Part I: Synthesis of the Z-isomer (Precursor of AsymmetricHydrogenation)

Preparation PP27

[0876] Z-isomer 5 was synthesized as outlined in Scheme PI. Compound 5was shown to be a single isomer by HPLC and H-1 nmr. The double bondstereochemistry was derived from comparative NOE data using thepurported E-isomer (Scheme P1). The best chiral induction was achievedusing compound 8/Ferrotane/MeOH-THF. With regard to the conversion of 9to 10, which would constitute a formal asymmetric synthesis ofisoindolene 10, this has been achieved using Super hydride-BF₃.OEt₂.However, the product was a mixture of 10 and the corresponding de-BOC(deprotected) compound.

Preparation PP28

[0877] Compound 2 (scheme P1)

[0878] Phthalic anhydride (751.5 g, 5.014 mole), potassium acetate (498g, 5.014 mole) and acetic anhydride (1 L) were stirred together undernitrogen. The mixture was slowly warmed to 145-150° C. and stirred for10 minutes, then at 140° C. for 20 minutes. The mixture was allowed toslowly cool to 80° C. over 1 hour. Three volumes of water were addedcausing precipitation of a solid. After filtration, the filtered solidwas washed with warm water and pulled as dry as possible for 30 minutes.The solid was then washed with ethanol and acetone respectively. Ifrequired further purification could be achieved by slurrying the solidin acetone, at room temperature, for 15 minutes, then filtration. Dryingin vacuo at 50° C. for 20 hours gave compound 2 as an off-white solid,470 g (48%) with an NMR purity of approx. 90%.

Preparation PP29

[0879] Compound 3 (Scheme P1)

[0880] Compound 2 (470 g, 2.47 mole) was added to stirred aqueousammonia (470 ml conc. NH₃ in 4.7 L water). The resultant mixture wasstirred at room temperature for 1 hour then filtered. The filtered solidwas washed with water. The combined aqueous filtrate and washings werecarefully acidified with 6M aq. HCl (2.35 L). The precipitate wasremoved by filtration and dried in vacuo at 50° C. to give compound 3 asa yellow solid, 259 g (52%).

Preparation PP30

[0881] Compound 4 (Scheme P1)

[0882] Compound 3 (511 g, 2.7 mole) was slurried in toluene (10 vol).Thionyl chloride (385 g, 3.24 mole) was added over 10 minutes to thestirred mixture, which was then heated to reflux for 1.5 hours. H-1 NMRanalysis indicated approx. 80% conversion to acid chloride). DMF (3.7ml) was added and the mixture refluxed an additional 3 hours. Theresultant mixture was allowed to cool to 35° C. and methanol (1.27 L)added at such a rate that the reaction temperature was maintained at30-35° C. The reaction mixture was kept at this temperature a further 15minutes then concentrated in vacuo to give compound 4 as a brown solid,536 g (quantitative).

Preparation PP31

[0883] Compound 5 (Scheme P1)

[0884] Compound 4 (750 g, 3.65 mole) was dissolved in acetonitrile (15L) . The stirred mixture was cooled to 0-5° C. and DMAP (624 g, 5.11mole) added in one portion. After 10 minutes BOC anhydride (1115 g, 5.11mole) was added in one portion: there was a slight exotherm accompaniedby gas evolution. The mixture was stirred at room temperature for 5hours, and then concentrated in vacuo. The residue was dissolved inEtOAc and washed with 10% aqueous citric acid, satd. aq. Na₂CO₃ andwater respectively. After drying, concentration of the organics gave athick syrup. This material was run through a plug of silica gel (1.5 kg)eluting with 1:1 EtOAc-hexane. Compound 5 was isolated as a dark solid,619 g (55%). Careful chromatography on silica gel eluting with 20%EtOAc-hexane gave 5 as a fluffy white solid.

Scheme P2

[0885] Part II: Synthesis of the E-isomer (Precursor of AsymmetricHydrogenation)

Preparation PP32

[0886] The E-isomer of Compound 8 (Scheme P2) was prepared as shown inScheme P2.

Preparation PP33

[0887] Compound 7 (Scheme P2)

[0888] The compound 7 was prepared according to the procedure of Einhornet al, Synth. Commun. 2001, 31(5), 741-748.

Preparation PP34

[0889] Compound 8 (Scheme P2)

[0890] Compound 7 (15.00 g, 60.7 mmole) and methyl(triphenylphosphoranylidene) acetate (41.40 g, 121.3 mmole) were slurred intoluene (150 ml). The mixture was stirred at reflux and monitored forreaction of 7 by GC. After 1.5 hours the reaction appears complete byGC. After cooling to room temperature, the mixture was filtered. Thesolid on the filter was washed with toluene until colorless. Thecombined filtrate/washings were concentrated in vacuo to leave a tansolid. This material was coated on silica gel and chromatographed onsilica gel (1 kg) eluting with 10% EtOAc-hexane. Compound 8 was isolatedas a white or pale yellow powder, 5.52 g (30%).

Preparation PP35

[0891] Screening of chiral hydrogenation conditions indicated that thebest chiral induction was achieved using compound 8/Ferrotane/MeOH-THF.With regard to the conversion of 9 to 10, which would constitute aformal asymmetric synthesis of isoindolene 10, this has been achievedusing Super hydride-BF₃.OEt₂. However, the product was a mixture of 10and the corresponding de-BOC (deprotected) compound.

Scheme P4

[0892] Coupling of Chiral Isoindoline With D-4-chloro-phenylalanineUsing Tartrate Salt:

Preparation PP36

[0893] Compound 15 (Scheme P4)

[0894] Tartrate salt 14 (58.00 g, 100.27 mmole) was slurried in water(580 ml) . Solid NaHCO₃ (25.27 g, 300.8 mmole) was carefully added. BOCanhydride (22.98 g, 105.28 rnmole) was added in one portion and theprogress of the reaction monitored by reverse phase HPLC. After 1 houradditional BOC anhydride (2.18 g, 10.00 mmole) was added. The reactionwas complete (by HPLC) after 3 hours. The mixture was extracted withEtOAc (2×250 ml). The combined organic extracts were washed with water(250 ml) and dried (MgSO₄). Filtration and concentration in vacuo gave15 as a clear light brown oil (31.33 g) contaminated with a small amountof t-BiOH and BOC anhydride. This material was used directly in the nextreaction.

Preparation PP37

[0895] Compound 16 (Scheme P4)

[0896] Ester 15 (29.21 g, 100.26 mmole) was dissolved in 3:1 THF-water(100 ml). LiOH (6.00 g, 250.65 mmole) was added in 1 portion to thestirred solution. After 17 hours, the mixture was stripped to drynessand the residue dissolved in water (500 ml). EtOAc (250 ml) was addedand solid NaHSO₄ added to the stirred mixture until the pH=3. Theorganic layer was separated and the aqueous layer extracted with EtOAc(250 ml). The combined EtOAc layers were dried (MgSO₄) Filtration andconcentration in vacuo gave acid 16 as a light tan solid, 27.10 g (97%).

[0897] The chemistry used is shown in Scheme P5. Two protocols wereused: method A used isolated 16, method B used a solution of 16 derivedfrom resolved salt 19.

Preparation PP38

[0898] Compound 17 (Scheme P5, method A)

[0899] Acid 16 (24.18 g, 87.2 mmole) and D-chloro-phenylalaninehydrochloride (21.81 g, 87.2 mmole) were dissolved in CH₂Cl₂ (100 ml)and DMF (25 ml). The mixture was stirred at ambient temperature. HOBT(13.55 g, 100.3 mmole) and Hunig's base (45.6 ml, 33.81 g, 261.6 mmole)were added. HATU (38.13 g, 100.3mmole) was added in 1 portion (there wasa rapid exotherm to 50° C.). The mixture was stirred for 90 minutes thendiluted with EtOAc (750 ml). The resulting mixture was washed withwater, 5% KHSO₄, brine and satd. NaHCO₃ respectively, then dried.Filtration and concentration in vacuo gave crude 17 as a brown foam. Theproduct was purified by chromatography on silica gel (lkg) eluting with1:1 EtOAc-hexane. Ester 17 was isolated as a tan powder, 38.85 g (94%).

Preparation PP39

[0900] Compound 17 (Scheme P5, method B)

[0901] Resolved salt 19 (96.27 g, 232.5 mmole) was partitioned betweenwater (500 ml) and CH₂Cl₂ (250 ml) Solid KHSO4 was added portion wiseuntil pH=2.5. Separate the organic layer and extract the aqueous layerwith CH₂Cl₂ (150 ml). The combined organic layers were dried (MgSO₄)then filtered. To this solution was added 4-chloro-D-phenylalanine(58.16 g, 232.5 mmole), HOBT (34.57 g, 255.8 mmole), Hunig's base (93.2ml, 69.13 g, 534.9 mmole) and finally HATU (97.26 g, 255.8 mmole). Theresultant mixture was stirred at room temperature for 18.5 hours, andthen poured onto a plug of silica gel (1 kg). This was washed with 1:1EtOAc-hexane until no more product elutes. Ester 17 was isolated as apink foam, 101.79 g (93%): contains about 1% unreacted 16.

Preparation PP40

[0902] Compound 18 (Scheme P5)

[0903] Ester 17 (38.64 g, 81.7 mmole) was dissolved in 3:1 THF-water(200 ml). LiOH (2.15 g, 89.9 mmole) was added to the mixture, which wasstirred at room temperature for 2 hours. The solvent was then removed invacuo and the residual solid taken up in water (600 ml). This wasextracted with MTBE (250 ml). The aqueous layer was separated andstirred with EtOAc (250 ml), and solid KHSO₄ was added portion wiseuntil pH=3. The layers were separated and the aqueous extracted withEtOAc (250 ml). The combined organic layers were dried over MgSO₄.Filtration and concentration in vacuo gave acid 18 as a light pink foam,38.41 g (35.71 g corrected for residual solvent, 95%).

Preparation PP41

[0904] Step 1: Esterification

[0905] In a 22 L 4-neck round bottom flask equipped with a refluxcondenser, thermocouple and nitrogen inlet, a slurry of 1000 g (5.4moles) of m-tyrosine in 10 L of 2B-3 EtOH was cooled to 5° C. To theslurry, 350 mnL (12.4 moles) of thionyl chloride were added dropwise viaan addition funnel at such a rate to maintain the reaction temperaturebelow 20° C. Upon completion of addition, the reaction was heated toreflux temperature and stirred for 18 hrs. The reaction was concentratedto one-third the volume and 8 L of MTBE were charged. The resultingthick slurry was stirred for 14 hrs in a rotary evaporator at rt. Theresulting solid was isolated on a filter pad and dried at 40° C. for 48hrs yielding 1288 g (95%). NMR (DMSOd₆) indicated desired material.

Preparation PP42

[0906] Step 2: Pictet-Spengler

[0907] In a 22 L 4 neck round bottom flask equipped with a mechanicalstirrer, thermocouple, and reflux condenser placed on top of a Soxhletextractor charged with 4° A sieves, a semi-solution of m-tyrosine ethylester hydrochloride 1288 g (5.26 moles) in 13 L of acetone was heated toreflux temperature. The condensate was filtered through the sieves toremove water. The reaction was stirred vigorously at reflux for 48 hrs.An NMR sample in DMSOd₆ indicated the absence of starting material. Thereaction was cooled to rt and concentrated to yield an off-white solid,1411 g (94%).

Preparation PP43

[0908] Step 3: Triflation

[0909] In a 22 L 4 neck round bottom flask equipped with a refluxcondenser, mechanical stirrer, nitrogen inlet, and a thermocouple, 1240g (4.35 moles) of the starting material salt in 12.4 L of methylenechloride was cooled to 4° C. To the mixture, 1452 mL (10.4 moles) oftriethylamine were added and stirred into solution. Triflic anhydride,1472 mL (5.22 moles) was added dropwise to the reaction at such a rateto maintain the internal temperature below 10° C. The ice bath wasremoved and the reaction warmed to rt. and stirred for 18 hrs. Thereaction was concentrated to a oil then dissolved in 4 L of EtOAc andconcentrated again to an oil in an effort to remove excess triflicanhydride The crude residue was dissolved in 4 L of EtOAc and washedwith water and saturated sodium bicarbonate solution. The organic layerwas isolated and dried with sodium sulfate, filtered and concentrated toyield 1720 g (>100%) of a crude dark oil which was used without furtherpurification.

Preparation PP44

[0910] Step 4: Deoxygenafion

[0911] A solution of 1720 g (4.35 moles) of crude starting material in14 L of acetone was charged to a 10 gallon stainless steel autoclave. Tothe solution, a slurry of 5% Pd/C in 1.2 L of toluene was added. Thereaction mixture was evacuated and purged with H₂ gas at 50 psi twotimes. The reaction was stirred overnight at 50° C. with H₂ at 50 psi. Asample aliquot indicated no reaction had occurred. The mixture wasfiltered and concentrated to a thick oil and resubjected to reactionconditions. After 18 hrs, NMR of a sample aliquot indicated absence ofstarting material. The reaction mixture was filtered and the filtrateconcentrated to yield 1581 g of an off-white solid (95%).

Preparation PP45

[0912] Step 5: Hydrolysis/Salt Formation

[0913] To a 2 L 3 neck round bottom flask equipped with a mechanicalstirrer, thermocouple, and nitrogen inlet, a mixture of 700 g (1.83moles) of the triflate salt starting material was charged. A solution of427 g (1.83 moles) of the starting material free base in 13.3 L of THFwas added followed by 700 mL of water. The semi-solution was stirredvigorously at rt. To the reaction flask, 43.7 g (1.83 moles) of solidLiOH were added in small portions at such a rate to maintain theinternal temperature below 35° C. The reaction was stirred for 18 hrs atrt and concentrated to yield a thick oil. THF (4 L) was added and thesemi-solution was concentrated. This was repeated with toluene and thesemi-solid was placed under house vacuum on the roto vap with stirringfor 18 hrs to yield 650 g of a crude solid. The solid was reslurried inEtOAc, filtered, isolated and dried to yield 525 g (68%) of the lithiumsalt as an off-white solid.

Preparation PP46

[0914] Step 6: Coupling

[0915] To a 12 L 4 neck flask equipped with a mechanical stirrer,water-cooled reflux condenser, thermocouple, and nitrogen inlet, amixture of 400 g (1.62 mole) of the starting material free acid, 2 L ofDMF, and 2 L of methylene chloride was stirred vigorously. Solidd-chloro-phenylalanine 446 g (1.78 moles) was added to the semi-solutionfollowed by 20 g (0.162 moles) of DMAP. The resulting mixture wasstirred for 15 minutes then solid EDCl(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) 390 g(2.03 moles) was added. The reaction mixture was heated to 80° C. andstirred for 18 hours. Thin layer chromatography (1:1 EtOAc:Hex)indicated very little starting material present. The reaction was cooledto rt and concentrated to yield a thick oil. The crude oil was dissolvedin EtOAc and washed with water, and brine. The solution was dried withsodium sulfate, filtered and concentrated to yield a thick oil, 426 g.The crude oil was chromatographed in several lots using a Waters Prep500 chromatography apparatus. The eluent consisted of a gradient system,5%-80% EtOAc in heptane at a flow rate of 240 ml/min over 38 minutes.The two diasteromers were separated and isolated to yield 119.04 g forthe top spot and 111.3 g for the bottom spot. Conformation of bothdesired diastereomers was achieved via NMR (DMSO₆).

Preparation PP47

[0916] Resolution of tetrahydroisoquinolinecarboxylic acid ethyl esterto prepare 1-tartaric acid salt:

[0917] Preparation of free-base: A racemic mixture oftetrahydroisoquinolinecarboxylic acid (7.43 g) in EtOAc (60 mL) wastreated with saturated NaHCO₃ solution (60 mL) and saturated Na₂CO₃solution (10 mL). The mixture was agitated and the layers weresepararted. The organic phase was dried (Na₂SO₄) and concentrated togive the corresponding free-base as an oil (4.85 g)

[0918] Resolution: A mixture of the above free base (467 mg, 2.0 mmol),and L-tartaric acid (300 mg, 2.0 mmol) in acetone (4 mL) was stirred atRT overnight. The title L-tartaric acid salt was collected byfiltration, washed with acetone (about 2 mL) and dried to a white powder(367 mg). 100% ee by chiral CE.

Preparation PP48

[0919] Resolution of N-BOC Tetrahydroisoquinolinecarboxylic Acid

[0920]2-{2-[(tert-butyl)oxycarbonyl]-1,2,3,4-tetrahydroisoquinolyl}acetic aciddehydroabietylamine salt: Racemic2-{2-[(tert-butyl)oxycarbonyl]-1,2,3,4-tetrahydroisoquinolyl}acetic acid(30.15 g, 103.5 mmol) was dissolved in i-PA (300 mL).Dehydroabietylamine (22.11 g, 52.7 mmnol of a 68 weight % mixture) wasadded to the solution, which was then agitated on a multi-arm shaker for63 h. The resultant thick paste was filtered and rinsed with i-PA (50mL, 25 mTL). Dried in a 50° C. vacuum oven to obtain a white solid(27.73 g, 52% ee by chiral CE analysis). The product was reslurried ini-PA (266 mL) and agitated on a multi-arm shaker for 23.5 h. Filteredthe thick slurry and rinsed with cold i-PA (50 mL, 30 mL). Dried thecake in a 50° C. vacuum oven and obtained the product as a white solid(23.63 g, 40% yield, 94% ee by chiral CE analysis).

Preparation PP49

[0921] Enamine 21 (Scheme P6) was prepared as a substrate for asymmetrichydrogenation screening studies. It is formed as an approx. 10:1 mixturewith imine 22. The enamine (21) may be NH-protected i.e. by a Bocprotecting group. The resulting compound 23 may be subjected toasymmetric hydrogenation to afford the acetic acid or methylacetatesubstituted isoquinoline, which may be processed into a compound offormula I as demonstrated previously.

Preparation PP50

[0922] Compound 21 (Scheme P6)

[0923] Prepared as published W Sobotka et al, J. Org. Chem., 1965, 30,3667

Preparation PP51

[0924] The chiral synthesis of gem-dimethyl TIC using L-Dopa as thestarting material instead of tyrosine was successfully demonstrated upto the Pictet-Spengler reaction with L-DOPA and acetone. The product isa mixture of starting material 24 and product 25 (major component). Theproduct was isolated by using common isolation procedures. Analternative isolation method is to react the mixture (24 and 25) withBOC anhydride wherein the less hindered N-H in 24 leads to preferentialBOC protection of 24, allowing for ready separation of 25. Chemistry forthe rest of the sequence i.e. deoxygenation reaction, has beendemonstrated herein.

Preparation of Novel “B-C” Domain Pieces Preparation BC1

[0925]

[0926]3-[2-(4-Chloro-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

[0927] A. To a 0° C. solution of 4-Chloro-D-Phe methyl ester (23.8 g,111.0 mmol), Boc protected D-Tic (30.8 g, 111.0 mmol) and 4-DMAP (75 mg,0.61 mmol) in 200 mL of DCM was added EDC (30.8 g, 111.0 mmol) and themixture stirred for 20 minutes. The ice bath was removed and the mixturestirred at room temperature for 4 h. After washing with water (4×200mL), the combined aqueous portions were back extracted with DCM (2×200mL). The combined organic portions were washed with brine, dried(MgSO₄), and concentrated to dryness. The desired product was purifiedby flash chromatography (SiO₂, eluting with 35% EtOAc in Hexanes)affording 43.0 g (83%) of the ester. EIS MS 473 [M+1].

[0928] B. To the above formed ester (43.0 g, 91.0 mmol), in MeOH (170mL) at 0° C., was added 1N NaOH (227.0 mL, 227.0 mmol), dropwise. After20 minutes the ice bath was removed and the mixture stirred at roomtemperature for 3 h. The mixture was concentrated to dryness, and theresulting residue suspended in 200 mL of water. The aqueous layer wasmade acidic (pH 1) with 5 N hydrochloric acid and extracted with EtOAc(4×200 mL). The combined organics were dried (MgSO₄), filtered, andconcentrated to dryness, affording 39.0 g (93%) of the title compound.EIS-MS 459 [M+1].

Preparation C1

[0929]

[0930] 1-Methoxycarbonylmethyl-1,3-dihydro-isoindole-2-carboxylic acidtert-butyl ester

[0931] A. (2-Bromo-benzyl)-carbamic acid tert-butyl ester:

[0932] To 2-bromobenzylamine hydrochloride (125.0 g, 561.8 mmol), inTHF/water (1:1, 300 mL), was added potassium carbonate (170.7 g, 1236.0mmol) and di-tert-butyl dicarbonate (134.9 g, 618.0 mmol), in fourportions over 20 minutes. The mixture was stirred atroom temperature for16 h and diluted with 300 mL of EtOAc and 300 mL of water. The organicportion was separated and the aqueous portion was extracted with EtOAc(3×200TmL). The combined EtOAc portions were washed with 250 mL of 10%aqueous sodium bisulfate, dried (MgSO4), and concentrated to dryness toafford 161.0 g of the title compound.

[0933] B. 3-[2-(tert-Butoxycarbonylamino-methyl)-phenyl]-acrylic acidmethyl ester:

[0934] To the product from part A (161.0 g, 561.8 mmol), in DMF (800mL), was added methyl acrylate (58.0 g, 674.2 mmol), TEA (170.5 g,1685.4 mmol), and dichlorobis(triphenylphosphine)palladium(II) (7.9 g,11.2 mmol) and the mixture was heated at 80° C. for 32 h. The mixturewas cooled, diluted with 1000 mL of EtOAc and washed with 10% aqueoussodium bisulfate. The aqueous portion was extracted three times withEtOAc and the combined organics were dried(Na₂SO₄) and concentrated todryness. The residue was dissolved in a small amount of DCM and filteredthrough 7 in. of silica gel in a 2 L sintered glass funnel eluting with25% EtOAc/hexanes. The eluent was concentrated to dryness andrecrystallized from EtOAc/hexanes to afford 116.9 g (71%) of the titlecompound.

[0935] C. To a 0° C. solution of the material from Part B (116.9 g,401.2 mmol) in 800 mL of DCM was added 200 mL of TFA dropwise over 15min. After removing the cooling bath, the mixture was stirred for 2.5 hand concentrated to dryness. The residue was dissolved in 500 mL of DCMand saturated aqueous sodium bicarbonate was slowly added until themixture was slightly basic. The organic portion was separated and theaqueous portion was extracted two times with DCM. The combined organicportions were dried (Na₂SO₄) and concentrated to dryness. The residuewas dissolved in 800 mL of DCM and to the mixture was added DIPEA (57.,0g, 441.4 mmol) and di-tert-butyl dicarbonate (96.3 g, 441.4 mmol) infive portions over 45 minutes and the mixture stirred at roomtemperature for 16 h. The mixture was washed with 10% aqueous sodiumbisulfate, the organic portion was separated and the aqueous portionextracted two times with DCM. The combined organic extracts were dried(Na₂SO₄) and concentrated. The residue was dissolved in a small amountof DCM and filtered through 7 in. of silica gel in a 2 L sintered glassfunnel eluting with 25% EtOAc/hexanes. The eluent was concentrated todryness and the enantiomers separated by chiral chromatography(Chiralcel OD). The first eluting isomer was labeled isomer #1 and thesecond eluting isomer #2; affording 52.6 g (45%) of the title compound(isomer 2).

[0936] EIS-MS 292 [M+1].

Preparation C2

[0937]

[0938] 1-Carboxymethyl-1,3-dihydro-isoindole-2-carboxylic acidtert-butyl ester

[0939] To the product from Preparation Cl (52.6 g, 180.5 mmol), in MeOH(500 mL), was added 1 N NaOH (199 mL, 199.0 mmol). The mixture wasstirred at room temperature for 48 h and then concentrated to dryness.The resulting residue was dissolved in water (300 ml,) and extractedwith diethyl ether (2×). The aqueous portion was acidified to pH 2 with10% aqueous sodium bisulfate and extracted with EtOAc. The combinedorganic extracts were dried (MgSO₄) and concentrated to dryness. Yield:49.8 g, 99%. EIS-MS 276 [M−1].

Preparation BC2

[0940]

[0941]1-{[1-Carboxy-2-(4-chloro-phenyl)-ethylcarbamoyl]-methyl}-1,3-dihydro-isoindole-2-carboxylicacid tert-butyl ester

[0942] A. To a suspension of 4-Cl-D-Phe methyl ester hydrochloride (40.4g, 161.5 mmol), in DCM (250 mL), was added saturated aqueous sodiumbicarbonate (250 mL) and the mixture stirred at room temperature for 1h. The organic portion was separated and the aqueous portion wasextracted with DCM (2×). The combined organic portions were dried(Na₂SO₄) and concentrated to dryness To the free amine, in DCM (400 mL)at 0° C., was added example C₂ (isomer 2, 44.8 g, 161.5 mmol), EDC (31.0g, 161.5 mmol) and 4-DMAP (2.0 g, 16.1 mmol). The reaction mixture wasstirred at 0° C. for 30 minutes whereupon the cooling bath was removedand the reaction mixture was stirred for another 5 h at roomtemperature. The mixture was then washed with saturated aqueous sodiumbicarbonate (200 mL), 10% aqueous sodium bisulfate (200 mL), dried(Na₂SO₄), and the organic phase was concentrated to dryness to afford76.4 g (100%) of the ester. EIS-MS 471 [M−1].

[0943] B. To the ester from Part A (76.4 g, 161.5 rmnol), in MeOH (760mL), was added 1 N NaOH (242.0 mL, 242.0 mmol) and the mixture heated at50° C. for 4 h. then stirred for another 16 h at room temperature. Afterconcentrating to dryness, the resulting residue was taken up in 500 mLof water and washed with diethyl ether (2×). The aqueous portion wasacidified to pH 2 with 10% aqueous sodium bisulfate and extracted withEtOAc (4×200 mL). The combined organic extracts were dried (MgSO₄) andconcentrated to dryness. The resulting solid was suspended in hexanes,filtered, and dried to afford 67.7 g (91%) of the title compound.

[0944] EIS-MS 457 [M−1].

Preparation C3

[0945]

[0946] 1-Carboxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester, lithium salt

[0947] A. (1,2,3,4-Tetrahydro-isoquinolin-1-yl)-acetic acid methyl ester

[0948] To Boc-tetrahydoisoquinoline-1-acetic acid (100.4 g, 520.0 mmol),in MeOH (200 mL), was added 400 mL of 2.3 M HCl in methanol. The mixturewas stirred overnight and then concentrated to dryness. The resultingresidue was dissolved in EtOAc, washed with saturated sodiumbicarbonate, brine, dried (Na₂SO₄), and concentrated to dryness;affording 109.5 g (100%) of the ester.

[0949] EIS-MS 206 [M+1].

[0950] B.1-Methoxycarbonylmethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester

[0951] To a 0° C. solution of material from part A (50.5 g, 240.0 mmol),in ThF (250 mL), was added di-tert-butyl dicarbonate (59.3 g, 270.0mmol), in THF (50 mL), dropwise. After stirring 45 minutes, the mixturewas concentrated to dryness. The resulting residue was dissolved inEtOAc, washed with saturated sodium bicarbonate, brine, dried (Na₂SO₄),and concentrated to dryness. Chiral chromatography (Chiracel OD) of theresidue afforded both enantiomers, with the first eluting isomer labeledisomer 1 and the second isomer 2. EIS-MS 306 [M+1].

[0952] C. To a solution of material from part B (10.2 g, 33.4 mmol), indioxane (220 mL), was added a solution of lithium hydroxide monohydrate(1.67 g, 39.8 mmol), in water (110 mL), portionwise so as to maintain atemperature below 30° C. The mixture was stirred for 16 h and thenconcentrated to dryness; affording 11.2 g of the lithium salt.

[0953] EIS-MS 292 [M+1].

Preparation BC3

[0954]

[0955] Lithium2-[(2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-3-ylmethyl)-amino]-3-(4-chloro-phenyl)propionate

[0956] A. 3-(Methoxy-methyl-carbamoyl)-3,4-dihydro-1Hisoquinoline-2-carboxylic acid tert-butyl ester

[0957] To Boc-D-1,2,3,4-tetrahydroisoquinoline carboxylic acid (14.9 g ,53.7 mmol), in THF (500 mL), was added N,O-dimethylhydroxylaminehydrochloride (5.24 g, 53.7 mmol), EDC (11.3 g , 59.1 mmol), HOBT (7.98g, 59.1 mmol) and DIPEA (9.83 ml, 56.4 mmol) The mixture was stirred for16 h, at room temperature and under nitrogen and then concentrated todryness. The resulting residue was taken up in EtOAc, washed with 1MHCl, saturated sodium bicarbonate, brine, and dried (Na₂SO₄). Afterconcentrating to dryness, the resulting residue was purified by flashchromatography (SiO₂, eluting with 1:1 EtOAc/hexane) to give 12.3 g(71%) of the ester. EIS-MS 321 [M+1).

[0958] B. 3-Formyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester:

[0959] To a 0° C. solution of material from part A (1.28 g, 4.00 mmol)in THF (30 mL), was slowly added 1.0 M LAH (in THF, 5.1 ml, 5.1 mmol) .The reaction mixture was stirred at 0° C. for another 15 minutes. To themixture was slowly added 20 mL of 5% aqueous potassium hydrogensulfateand the mixture extracted with Et₂O (2×). The combined organic portionswere washed with 1M hydrochloric acid, saturated sodium bicarbonate,brine, dried (Na₂SO₄), and concentrated to dryness; affording 0.78 g(75%) of the title compound.

[0960] EIS-MS 262 [M+1].

[0961] C.3-{[2-(4-Chloro-phenyl)-1-methoxycarbonyl-ethylamino]methyl}-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester:

[0962] To a 0° C. solution of 4-Cl-D-Phe methyl ester (6.27 g , 25.1mmol) and sodium acetate (8.23 g, l00.Ommol), in 850 ml dry MeOH, wasadded material from part B (9.8 g, 37.6 mmol), in 50 ml MeOH. Themixture was stirred for 15 minutes and then sodium cyanoborohydride(2.37 g, 37.6 mmol) added. The cooling bath was removed and the reactionstirred for 16 h at room temperature. The mixture was concentrated todryness and the resulting residue taken up in water and iml of 1M HCl.The mixture was extracted with EtOAc and the organics washed withsaturated sodium bicarbonate, brine, dried (Na₂SO₄), and concentrated todryness. The resulting residue was purified by flash chromatography(SiO₂, eluting with 2:1 hexane/EtOAc) affording 8.62 g (75%) of thetitle compound. EIS-MS 459 [M+1].

[0963] D. To a 12° C. solution of material from part C (1.11 g, 2.42mmol), in dioxane (15 ml), was added a solution of lithium hydroxide(0.10 g, 2.42 mmol), in water (7.5 mL). The mixture was stirred for 16 hand then concentrated to dryness; affording 1.08 g (100%) of the titlecompound.

[0964] EIS-MS 445 [M+1].

Preparation C4

[0965]

[0966] A. (1,2,3,4-Tetrahydro-isoquinolin-1-yl)-acetic acid methylester:

[0967] To the product from Preparation C3, part B (9.98 g, 32.7 mmol)was added 500 mL of cold 4M HCl in dioxane. After one hour, the mixturewas concentrated to dryness. The resulting residue was dissolved inEtOAc, the organics washed with saturated sodium bicarbonate, brine,dried (Na₂SO₄), and concentrated to dryness; affording 6.9 g (100%) ofthe amine. EIS-MS 206 [M+1].

[0968] (2-Methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid methylester:

[0969] B. To the product from part A (6.71 g, 32.0 mmol), indichloroethane (175 mL), was added 37% aqueous formaldehyde (22.6 mL,300 mmol). After 10 minutes, sodium triacetoxyborohydride (31.2 g, 147.0mmol) was added in 2-3 g portions, with cooling maintain so as tomaintain ambient temperature. Upon completion of addition, the mixturewas stirred for 16 h at room temperature. DCM and water was then addedand the mixture adjusted to pH 9-10 with 5N NaOH. The organic layer wasseparated, washed with brine, dried (Na₂SO₄), and concentrated todryness. The resulting residue was purified by flash chromatography(SiO₂, eluting with DCM/2N ammonia in methanol, 95:5); affording 6.9 g(96%) of the title compound. EIS-MS 220 [M+1].

[0970] C. To part B (4.45 g, 18.9 mmol), in dioxane (120 mL), was addedlithium hydroxide monohydrate (1.02 g, 22.7 mmol), in water (65 mL)portion-wise; thereby keeping the temperature below 30° C. After 16 hthe mixture was concentrated to dryness; affording 8.12 g of the titlecompound. EIS-MS 206 [M+1].

Preparation C5

[0971]

[0972] A. (2,3-dihydro-1H-isoindol-1-yl)-acetic acid methyl ester:

[0973] To the product from Preparation C1 (11.75 g., 40.41 mmol), in DCM(50 mL), was added TFA (50 mL) dropwise. After 2 hr, the solution wasconcentrated to dryness and the resulting residue partioned withsaturated aqueous sodium bicarbonate (200 mL) and EtOAc (300 mL). Theorganic portion was separated and the aqueous layer was extracted withDCM (4×500 mL). The combined DCM extracts were combined, dried (Na₂SO₄),and concentrated to dryness to afford 3.97 g (51%) of the titlecompound.

[0974] B. (2-Isopropyl-2,3-dihydro-1H-isoindol-1-yl)-acetic acid methylester:

[0975] To the product from part A (0.50 g, 2.61 mmol), in dichloroethane(46 mL), was added acetone (1.76 mL, 24.01 mmol) and sodiumtriacetoxyborohydride (2.48 g., 11.74 mrol). After 6 h, the mixture wasdiluted with 1.0N NaOH (100 mL), the organic portion was separated andthe aqueous layer extracted with DCM (3×100 mL). The combined DCMextracts were combined, dried (MgSO₄), and concentrated to dryness toafford 0.60 g (99%) of the title compound. EIS-MS 235 [M+1].

[0976] C. To the product from part B (0.53 g., 2.30 mmol), in MeOH (5.1mL), was added 1.ON NaOH (2.53 mL, 2.53 mmol). After two days, thesolution was concentrated to dryness. The resulting residue was dilutedwith 1.0N HCl and water then loaded onto a strong cation exchange resin.The resin was washed with water, THF/water (1:1), water, and the producteluted from the resin with pyridine/water (1:9). The eluent wasconcentrated to dryness to afford 0.43 g (85%) of the title compound.EIS-MS 220 [M+1].

Preparation C6

[0977]

[0978] (2-Methyl-2,3-dihydro-1H-isoindol-1-yl)-acetic acid

[0979] A. (2-Methyl-2,3-dihydro-1H-isoindol-1-yl)-acetic acid methylester:

[0980] To the Boc carbamate removed, as described in Step A ofPreparation C5, product from Preparation C1 (0.50 g, 2.61 mmol), indichloroethane (46 mL), was added 37% aqueous formaldehyde solution(1.80 mL, 24.01 mmol) and sodium triacetoxyborohydride (2.48 g., 11.74mmol). After 3 days, the mixture was diluted with 1.0N NaOH (100 mL).The organic portion was separated and the aqueous layer extracted withDCM (3×100 mL). The combined DCM extacts were dried (Na₂SO₄) andconcentrated to dryness. The resulting residue was purified by flashchromatography (SiO₂, eluting with 100% EtOAc); affording 0.43 g (79%)of the alkylated isoindole. EIS-MS 206 [M+1].

[0981] B. To the product from part A (0.34 g., 1.66 mmol), in MeOH (3.7mL), was added 1.0N NaOH (1.82 mL, 1.82 mmol). After 2 days, thesolution was concentrated to dryness. The resulting residue was dilutedwith 1.0N HC₁ and water then loaded onto a strong cation exchange resin.The resin was washed with water, THF/water (1:1), water, and the producteluted from the resin with pyridine/water (1:9). The eluent wasconcentrated to dryness to afford 0.31 g (98%) of the title compound.EIS-MS 192 [M+1].

Preparation C7

[0982]

[0983] (2-Butyl-2,3-dihydro-1H-isoindol-1-yl)-acetic acid

[0984] A. (2-Butyl-2,3-dihydro-1H-isoindol-1-yl)-acetic acid methylester:

[0985] To the Boc carbamate removed, as described in Step A ofPreparation C5, product from Preparation C1 (0.50 g, 2.61 mmol), indichloroethane (46 mL), was added butyraldehyde (2.16 mL, 24.01 mmol)and sodium triacetoxyborohydride (2.48 g., 11.74 mmol). After 3 days,the mixture was diluted with 1.0N NaOH (100 mL). The organic portion wasseparated and the aqueous layer extracted with DCM (3×75 mL). Thecombined DCM layers were dried (Na₂SO₄) and concentrated to dryness. Theresulting residue was purified by flash chromatography (SiO₂, elutingwith 1:3, EtOAc/hexanes); affording 0.5lg (77%) of the alkylatedisoindole. EIS-MS 249 [M+1].

[0986] B. To the product from part A (0.47 g., 1.89 mmol) in MeOH (4.2mL) was added 1.0N NaOH (2.08 mL, 2.08 mmol). After 2 days, the solutionwas concentrated to dryness. The residue was diluted with 1.0N HCl andwater then loaded onto a strong cation exchange resin. The resin waswashed with water, THF/water (1:1), water, and the product eluted fromthe resin with pyridine/water (1:9). The eluent was concentrated todryness to afford 0.28 g (64%) of the title compound. EIS-MS 234 [M+1].

Preparation C8

[0987]

[0988] Potassium (2-methyl-2,3-dihydro-1H-isoindol-1-yl)-acetate

[0989] To Preparation C6, part A (2.65 gm, 12.9 mmol), in THF (27 mL)was added potassium trimethylsilanolate (1.66 gm, 12.9 mmol) and thereaction stirred for two days. After concentrating to dryness theresulting thick solid was triturated with diethyl ether, filtered,washed with diethyl ether, and dried at room temperature to afford 2.73g (92%) of the title compound. EIS-MS 192 [M+1].

Preparation C9

[0990]

[0991] 7-Fluoro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-tert-butyl ester:

[0992] A. 2-Amino-3-(4-fluoro-phenyl)-propionic acid:

[0993] To N-Boc-4-Fluoro-D-Phe (2.37 g, 8.366 mmol), in MeOH, 3 mL ofconcentrated sulfuric acid was added. The reaction mixtured was heatedto reflux overnight then concentrated to dryness to afford the titlecompound. EIS-MS 198 [M+1].

[0994] B. 2-Ethoxycarbonylamino-3-(4-fluoro-phenyl)-propionic acid:

[0995] To a 0° C. mixture of material from part A (1.65 g, 8.37 mmol)and pyridine (1.35 mL, 17.4 mmol), in DCM, was slowly added ethylchloroformate (0.85 mL, 8.87 mmol). After 30 minutes the mixture waspartitioned between water and EtOAc. The aqueous layer was extractedwith EtOAc (2×). The combined organic extracts were dried (MgSO₄) andconcentrated to dryness to afford 2.17 g (96%) of the title compound.EIS-MS 270 [M+1].

[0996] C. 7-Fluoro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-ethyl ester:

[0997] A mixture of material from part B (2.17 g, 8.06 mmol),paraformaldehyde (0.254 g, 8.46 mmol), and 10 mL of 3:1 glacial aceticacid/concentrated sulfuric acid was stirred at room temperature for 48h. The mixture was then partitioned between water and EtOAc. The organicportion was separated and the aqueous layer extracted with EtOAc(3×).The combined EtOAc extracts were dried (MgSO₄), and concentrated todryness. Flash chromatography of the resulting residue (SiO₂, elutingwith 25% EtOAc/Hexane); affording 1.31 g (58%) of the title compound.EIS-MS 282 [M+1].

[0998] D. 7-Fluoro-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid:

[0999] The product from Part C (1.31 g, 4.656 mmol), in 20 mL of 5N HCl,was heated at reflux for 24 h. The solution was then concentrated todryness. The resulting white solid was washed with Et₂O to afford 0.87 g(81%) of the title compound. EIS-MS 196 [M+1].

[1000] E. To the product from part D (0.87 g, 3.75 mmol), in 20 ml of1:1 dioxane/water, was added Di-t-butyl-dicarbonate (0.90 g, 4.13 mmol)and TEA (2.36 mL, 16.90 mmol). The mixture was stirred at roomtemperature for 16 h and then diluted with EtOAc. The organic portionwas separated and the aqueous layer extracted with EtOAc (3×). Thecombined organic portions were dried (MgSO₄) and concentrated to drynessto give 0.64 g (58%) of the title compound. EIS-MS 294 [M+1].

Preparation C10

[1001]

[1002] 3-Methyl-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-tert-butyl ester

[1003] The compound of Preparation C10 was prepared fromα-methyl-D,L-Phe by following the substantially similar proceduredescribed in Preparation C9; yielding 1.7 g, of the title compound.EIS-MS 292 [M+1].

Preparation C11

[1004]

[1005] 3-[2-(tert-Butoxycarbonylarnino-methyl)-phenyl]-but-2-enoic acidethyl ester

[1006] N-Boc-2-bromobenzylamine (7.15 g, 25 mmol) was dissolved intotributylamine (12 mL) and degassed under vacuum. Palladium acetate (224mg, 1 mmol) and tri-o-tolylphosphine (608 mg, 2 mmol) was then added andthe mixture degassed under vacuum. Trans-ethylcrotonate (6.25 mL, 50mmol) was then added and the mixture was degassed with nitrogen. Thetube was sealed and the mixture was heated to 110° C. for 48 h. Thesolution was cooled to room temperature, diluted with diethyl ether (200mL) and filtered through celite. The solution was washed with 1N HCl(2×50 mL) and brine (50 mL) dried over magnesium sulfate andconcentrated to dryness. Flash chromatography (9:1 hexanes/ethylacetate) gave the title compound as a yellow oil (1.6 g, 20%). ¹H NMR7.22-7.37 (m, 3H), 7.08 (dd, J=7.4, 1.6 Hz, 1H), 5.75 (d, J=1.3 Hz, 1H),4.29-4.31 (m, 2H), 4.20 (q, J=7.1 Hz, 2H), 2.45 (d, J=1.3 Hz, 3H), 1.44(s, 9H), 1.30 (t, J=7.1 Hz, 3H).

Preparation C12

[1007]

[1008] (1-Methyl-2,3-dihydro-1H-isoindol-1-yl)-acetic acid ethyl ester

[1009] To Preparation C11 (1.6 g, 5 mmol), in CH₂Cl₂, was added TFA (10mL). The mixture was stirred for 1 h at room temperature andconcentrated to a yellow oil. TEA (5 mL) was added and the solution wasstirred for 15 minutes and concentrated to dryness. Purification byflash chromatography (Sio2, eluting with 5% 2N NH₃ in MeOH/EtOAc) gavethe title compound as a clear oil (1.0 g, 92%).

Preparation C13

[1010]

[1011]1-Ethoxycarbonylmethyl-1-methyl-1,3-dihydro-isoindole-2-carboxylic acidtert-butyl ester

[1012] (1-Methyl-2,3-dihydro-1H-isoindol-1-yl)-acetic acid ethyl ester(1.0 g, 4.6 mmol) and di-tert-butyl dicarbonate (1.1 g, 5.06 mmol) weredissolved into DCM (10 mL) under nitrogen atmosphere. The solution wascooled to 0° C. followed by dropwise addition of TEA (0.71 mL, 5.06mmol). The solution was warmed to room temperature and stirred 72 h. DCM(50 mL) was added and the solution washed with saturated sodiumbicarbonate (5 mL), H₂O (5 mL) and brine (5 mL). The organic phase wasdried over magnesium sulfate and concentrated to a clear oil.Purification by flash chromatography (SiO₂) gave the title compound as aclear oil (1.18 g, 81%). 1H NMR (CDCl3) δ 7.10-7.30 (m, 4H), 4.65-4.70(m, 2H), 3.84-3.92 (m, 2H), 3.42-3.48 (m, 0.5H), 2.65-2.80 (m, 1.5H),1.75 (s, 1.6H), 1.68 (s, 1.4H), 1.55 (s, 5H), 1.48 (s, 4H).

Preparation C14

[1013]

[1014] 1-Carboxymethyl-1-methyl-1,3-dihydro-isoindole-2-carboxylic acidtert-butyl ester

[1015] Compound of Preparation C13 (1.14 g, 3.56 mmol) was dissolvedinto ethanol (10 mL) and H₂O (2 mL) and cooled to 0° C. Lithiumhydroxide (470 mg, 11.1 mmol) was added and the mixture was stirred atroom temperature for 24 h. Lithium hydroxide (340 mg, 8 mmol) was addedand the solution was stirred for about 24 h. A 1 N solution of NaOH (5mL) was added and the solution was washed with hexanes (10 mL). Theaqueous solution was acidified with 1N HCl to pH 1. The solution wasextracted with EtOAc (3×20 mL), dried over magnesium sulfate andconcentrated to a white solid. The residue was recrystallized fromhexanes to give the title compound (850 mg, 82%). ¹H NMR (CDCl₃) δ7.10-7.30 (m, 4H), 4.60 (s, 2H), 3.65-3.80 (m, 0.6H), 3.30-3.40 (m,0.4H), 2.70-2.80 (m, 1H), 1.65-75 (m, 3H), 1.45-1.60 (m, 9H).

Preparation of C15

[1016]

[1017] 6-Fluoro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-tert-butyl ester

[1018] Compound C15 was prepared N-Boc-3-Fluoro-D-Phe by following thesame procedure as described in the Preparation of C9.

[1019] EIS-MS 294 [M+1].

Preparation BC4

[1020]

[1021] To 4-Chloro-D-Phenylalanine methyl ester hydrochloride (0.432 g,1.73 mmol) was added Compound of preparation C13 (0.504 g, 1.73 mmol),EDC (0.330 g, 1.73 mmol) and HOBT (0.233 g, 1.73 mmol). This wasfollowed by addition of dichloromethane (5 mL) and DIPEA (0.452 mL). Thesolution was stirred for 3 h then diluted with EtOAc (50 mL). Theorganics were washed with saturated NaHCO₃ (50 mL), water (50 mL), andconcentrated to dryness. The crude product was purified by flashchromatography (SiO₂, eluting with Hexane/EtOAc, 80:20) yielding 0.724g, 86% of the title compound as a white solid. EIS-MS 487.2 [M+1].

Preparation BC5

[1022]

[1023]3-(4-Chloro-phenyl)-2-[2-(1-methyl-2,3-dihydro-1H-isoindol-1-yl)-acetylamino]-propionicacid methyl ester.

[1024] To compound of Preparation BC4 in DCM (3 mL), was added TFA (3mL) and the mixture was allowed to stand for 2 h. After concentrating todryness, the diastereomers were separated by reverse phase HPLC [WatersSymmetry C18 column, eluting with H₂O (0.05% HCl)/CH₃CN, 90:10 to 60:40,following a straight line gradient]. The first eluting isomer waslabeled isomer 1 and the second isomer 2. EIS-MS 387.1 [M+1] for bothisomers.

Preparation BC6

[1025]

[1026]1-{[2-(4-Chloro-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]methyl}-1-methyl-1,3-dihydro-isoindole-2-carboxylicacid tert-butyl ester, isomer 1

[1027] To the compound of Preparation BC5 (isomer 1, 0.321 g, 0.831mmol), in THF/H2O 1:1, 4 mL) was added K₂CO₃ (0.253 g, 1.83 mmol) andBOC₂O. The mixture stirred for 12 h and then the crude mixture wasdiluted with EtOAc (25 mL), the organics washed with H₂O andconcentrated to dryness; yielding the title compound (0.33 g, 81%).EIS-MS 487.1 [M+1].

Preparation BC7

[1028]

[1029]1-{[2-(4-Chloro-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-methyl}-1-methyl-1,3-dihydro-isoindole-2-carboxylicacid tert-butyl ester, isomer 2

[1030] The compound of Preparation BC7 was prepared from the compound ofPreparation BC5 (isomer 2) by following the substantially similarprocedure described in Preparation BC6.

Preparation BC8

[1031]

[1032]1-{[1-Carboxy-2-(4-chloro-phenyl)-ethylcarbamoyl]-methyl}-1-methyl-1,3-dihydro-isoindole-2-carboxylicacid tert-butyl ester, isomer 1

[1033] To the product from Preparation BC6 (isomer 1, 0.330 g, 0.679mmol) in H₂O/THF 1:1 (10 mL) was added LiOH (0.050 g, 2.01 nmnol). Themixture was stirred for 5 h, then diluted with H₂O (50 mL) and acidifiedto pH 4 with 25% KHSO₄. The aqueous mixture was extracted with EtOAc(100 mL) and concentrated to dryness; yielding the title compound (0.335g). EIS-MS 473.2 [M+1].

Preparation BC9

[1034]

[1035]1-{[1-Carboxy-2-(4-chloro-phenyl)-ethylcarbamoyl]-methyl}-1-methyl-1,3-dihydro-isoindole-2-carboxyacid tert-butyl ester, isomer 2

[1036] Preparation BC9 was prepared from the compound of Preparation BC7(isomer 2) by following the substantially similar procedure described inPreparation BC8; yielding 0.26 g, 95% of the title-compound.

[1037] EIS-MS 473.3 [M+1].

Preparation BC10

[1038]

[1039]3-(4-Chloro-phenyl)-2-[(1,1-dimethyl-1,2,3,4-tetrahydro-isoquinoline-3-carbonyl)-amino]-propionicacid methyl ester

[1040] To a solution of 1,1-dimethyl TIC (240 mg, 1.17 mmol), 4-Cl-D-Phemethyl ester (322 mg, 1.28 mmol), HOBT (197 mg, 1.46 mmol), and DIPEA(0.81 mL, 44.68 mmol, 4.0 eq) in CH₂Cl₂/DMF (1:1) was added EDC (280 mg,1.46 mmol). The resulting mixture was stirred at room temperatureovernight. The reaction mixture was then diluted with EtOAc(100 mL),washed with saturated aqueous NaHCO₃, brine, dried (Na₂SO₄) andconcentrated to dryness. Purification and separation of diastereomers byflash chromatography (35 g SiO₂, linear gradient, 40 mL/min 10-50%EtOAc/hexane for 25 minutes and 50% EtOAc/hexane for 7 minutes) affordedtitle compound.

Preparation BC11

[1041]

[1042]3-(4-Chloro-phenyl)-2-[(1,1-dimethyl-1,2,3,4-tetrahydro-isoquiinoline-3-carbonyl)-amino]-propionicacid

[1043] To Preparation BC10 (5.95 g, 14.88 mmol), in a 1:1 mixture ofTHF/H2O (50 mL), was added lithium hydroxide hydrate (0.75 g, 17.87mmol). The reaction was stirred at room temperature for 18 h. Themixture was then concentrated to dryness. The resulting residue wasdissolved in water (50 mL), made acidic with 1N HCl (25 mL) and washedwith Et₂O (100 mL) The aqueous layer was evaporated to dryness, yielding6.18 g (98%) of the title compound. EIS-MS 387

Preparation BC12

[1044]

[1045]1-{[1-Carboxy-2-(4-chloro-phenyl)-ethylcarbamoyl]-methyl}-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester, isomer 1

[1046] A. To a solution of D-4-chlorophenylalanine methyl esterhydrochloride (883 mg, 3.53 mmol), Preparation C3 (isomer 1) (1.0 g,3.36 mmol), HOBT (568 mg, 4.2 mmol), and DIPEA (2.92 mL, 16.8 mmol) inCH₂Cl₂ (35 mL) was added EDC (805 mg, 4.2 mmol). The resulting mixturewas stirred at room temperature for 48 h. The reaction mixture waspoured into a mixture CH₂Cl₂-water (1:1) and the organic phase washedwith water (2×), dried (Na₂SO₄), filtered, and concentrated to dryness.Final purification by flash chromatography EtOAc-hexane (3:7) afforded1.38 g of desired compound as a white solid. MS m/z 485.2 (M⁺−1)

[1047] B. To a solution of the above-formed ester (1.38 g, 2.83 mmol) inTHF (15 ML), a 1M aqueous solution of LiOH.H₂O (14.15 mL, 14.15 mmol)was added and mixture stirred at room temperature for 1 h. Reaction wascooled to 0° C. and pH was adjusted to ≈1 upon addition of 1M HCl.Aqueous layer was extracted with EtOAc, dried (Na₂SO₄), and evaporatedto afford 1.32 g of the title compound as a white solid. MS m/z 471.2(M⁺−1)

Preparation BC13

[1048]

[1049]1-{[1-Carboxy-2-(4-chloro-phenyl)-ethylcarbamoyl]-methyl}-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester, isomer 2

[1050] The compound of Preparation BC13 was prepared from Preparation C3(isomer 2) by following a procedure substantially similar to thatdescribed in Preparation BC12.

[1051] MS m/z 471.2 (M⁺−1)

Preparation BC14

[1052]

[1053]3-(4-Chloro-phenyl)-2-[2-(2-methyl-2,3-dihydro-1H-isoindol-1-yl)-acetylamino]-propionicacid

[1054] A. To a solution of D-4-chlorophenylalanine methyl esterhydrochloride (1.37 g, 5.49 mmol), Preparation C6 (1.2 g, 5.23 mmol),HOBT (883 mg, 6.54 mmol), and DIPEA (4.55 mL, 26.2 mmol) in CH₂Cl₂ (35mL) was added EDC (1.25 g, 6.54 mmol). The resulting mixture was stirredat room temperature for 48 h. The reaction mixture was poured into amixture CH₂Cl₂-water (1:1) and the organic phase washed with water (2×),dried (Na₂SO₄), filtered, and concentrated to dryness. Finalpurification by flash chromatography (EtOAc, then EtOAc/MeOH/AcOH95:5:5) afforded 1.71 g of desired compound as a solid. MS m/z 387.1(M⁺+1)

[1055] B. To a solution of the above-formed ester. (1.71 g, 4.4 mmol) inTHF (40 mL), a IM aqueous solution of LiOH.H₂O (22.1 mL, 22.1 mmol) wasadded and mixture stirred at room temperature for 1 h. Reaction wascooled to 0° C. and pH was adjusted to &1 upon addition of 1M HCl.Aqueous layer was extracted with EtOAc, dried (Na₂SO₄), and evaporatedto afford 1.6 g of the title compound as a solid. MS m/z 373.2 (M⁺+1)

Preparation of Compound 3000

[1056] Procedure AAA

[1057] To a solution of Compound 3025 (4.00 g, 14.23 mmol) in THF (100mL) was added iso-butyl magnesium bromide 2 M in Et2O (21.34 mL, 42.69mmol) and stirred for 12 h. The mixture was then poured into water (200mL) and extracted with EtoAc (200, mL). The organics were separated andconcentrated to dryness. The title compound was collected cleanly without purification. Yield: 3.71 g, 84%, ES MS (M+1) 313.3

Preparation of Compound 3001

[1058] Procedure BBB

[1059] To a solution of 4-heptanal (5.00 g, 43.86 mrnol) andBoc-piperazine (8.16 g, 43.86 mmol) in MeOH (35 mL) was added aceticacid (2.63 g, 43.86 mmol) followed by NaCNBH3 (2.76 g, 43.86 mmol). Themixture was stirred for 12 h and concentrated to a thick oil. The crudemartial was diluted with water (300 mL) and extracted with EtoAc (200mL). The organics were separated and concentrated to dryness. The crudeproduct was purified by column chromatography (silica gel 60 mesh)eluting with Hexane/EtoAc (80/20). Yield 5.1 g, 41%, ES MS (m+l) 285.3

[1060] Procedures for preparing certain A-domain pieces are describedbeloew.

Preparation of Compound 3002

[1061] Procedure CCC

[1062] To α-bromo ethyl valerate (22.66 g, 108.37 mmol), was addedN-Boc-Piperazine (20.15 g, 108.37), Et₃N (15.2 mL, 108.37 mmol), THF(100 mL), and the mixture heated at reflux for 16 h. After cooling toroom temperature, the mixture was diluted with EtOAc (5 fold) and theorganics washed with saturated NaHCO₃, H₂O, and concentrated to dryness.The crude material was taken up in TFA (25 mL), stirred for 30 minutesand then concentrated to dryness. The resulting residue was taken up inH₂O, washed with EtOAc, and then the aqueous. layer made basic with SNNaOH and the desiredamine extracted into EtOAc. The organics wereconcentrated to dryness and the resulting residue taken up in THF/H₂O(1:1, 50 mL) and Boc₂O (7.25 g, 33.2 mmol), and K₂CO₃ (4.59 g, 33.2mmol) added and the mixture stirred for 2 h. After diluting with EtOAc(10 fold), the organics were washed with H₂O and concentrated todryness. The desired product was purified by flash chromatography (SiO₂,eluting with 10%EtOAc in Hexanes). Yield: 25.4 g, 75%. Ion spray MS:315.3 [M+H].

Preparation of Compound 3003

[1063] Procedure DDD

[1064] To compound 3002 (2.26 g, 7.18 mmol), in THF (25 mL), at 0° C.,was added LAH (0.571 g, 15.0 mmol) portionwise. Upon completion ofaddition the mixture was stirred for 1 h and then quenched, sequentiallywith 0.57 mL H₂O, 0.57 mL 15% NaOH, and 1.7 mL H₂O. The resultingaluminum salts were stirred at room temperature for 1 h and then removedby filtration. The filtrate was concentrated to dryness.

[1065] Yield: 1.65 g, 85%. Ion spray MS: 273.1 [M+H].

Preparation of Compound 3004

[1066] Procedure EEE

[1067] To compound 3003 (1.63 g, 5.98 mmol), in THF (10 mL), at 0° C.,was added PPh₃ (1.72 g, 6.58 mmol), phthalimide (1.15 g, 6.58 mmol), andthe mixture stirred for 10 minutes and then diethyl azodicarboxylate(1.04 mL, 6.58 mmol) added. Stirring was continued for 1 h and then themixture was diluted 10 fold with EtOAc and the organics washed with H₂O,brine, and concentrated to dryness. The desired product was purified byflash chromatography (SiO₂, eluting with 20% EtOAc in Hexanes). Yield:2.16 g, 90%. Ion spray MS: 402.2 [M+H].

Preparation of Compound 3005

[1068] Procedure FFF

[1069] To compound 3004 (2.15 g, 5.35 mmol), in EtOH (20 mL), was addedhydrazine (1.7 mL, 53.5 mmol) and the mixture heated at 60° C. for 30minutes. After cooling to room temperature, the suspension wasconcentrated to dryness and the resulting residue partitioned.betweenEtOAc and 1N NaOH. The organics were concentrated to dryness.

[1070] Yield: 1.36 g, 94W. Ion spray MS: 272.2 [M+H].

Preparation of Compound 3006

[1071] Procedure GGG

[1072] To compound 3005, in DMF (15 mL), was added K₂CO (3.43 g, 24.85mmol), and bromoethane (0.93 mL, 12.43 mmol). The mixture was stirred atroom temperature for 48 h and then diluted 10 fold with EtOAc. Theorganics were washed with H₂O and concentrated to dryness. The desiredproduct was purified by flash chromatography (SiO₂, eluting with 90:5:5,EtOAc-Et₃N-MeON). Yield: 1.23 g, 76%. Ion spray MS: 328.2 [M+H].

Preparation of Compound 3007

[1073] Procedure HHH

[1074] To a solution of KCN (1.61 g, 24.8 mmol) in H₂O (15 mL)N-Boc-piperazine (4.6 g, 24.6 mmol) was added and the mixture cooled to0° C. Then 1M aqueous HCl (23.9 mL, 23.9 mmol) was added followed bycyclohexanecarboxaldehyde (2.0 mL, 16.5 mmol) and the mixture stirredfor 20 h. It was poured over Et₂O and the aqueous phase extracted withEt₂O, dried (MgSO₄), and evaporated. The crude was purified by flashchromatography (hexane-EtOAc 4:1→3:1) to afford 4.2 g of 3007.

Preparation of Compound 3200

[1075] Procedure III

[1076]N-{1-(4-Chloro-benzyl)-2-[4-(1-cyclohexyl-3-methyl-butyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedihydrochloride salt.

[1077] A solution of 3102 as the dihydrochloride salt (332 mg, 1.21mmol), BC2 (638 mg, 1.39 mmol), 1-hydroxy-7azabenzotriazole (206 mg,1.51 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (574 mg, 1.51 mmol), and diispropylethylamine (2.1mL, 12.1 mmol) in CH₂Cl₂ (10 ML} and DMF (2.5 mL) was stirred at 23° C.for 16 h, diluted with CH₂Cl₂ and washed with brine, dried (Na₂SO₄), andevaporated. Purification by flash chromatography (hexaneEtOAc 4:1) gaverise to the coupled product. The Boc group was removed by stirring atroom temperature in methylene chloride/TFA (1:1, 20 mL) for 2 hours. Thesolvent was evaporated and the residue purified by a SCX cartridge(MeOH→2M NH₃ in MeOH). The resulting oil was dissolved in 0.1 M HCl inEtOAc and stirred for 10 min. Final evaporation of the solvent afforedthe desired product 3200. MS m/z 580 (M⁺+1).

[1078] The following compounds were prepared from a mono-protectedpiperazine and the appropriate ketone or aldehyde using proceduressubstantially similar to procedures C or HHH were appropriate. TABLE XXXCmpd. Analogous to # Structure procedure MS ES (m + 1) 3025

C 282.2 3026

C 268.2 3007

HHH 3028

C

[1079] The following compounds were prepared from the appropriateprecursor (see table) and procedures substantially similar to AAA, BBBor GGG were applicable. TABLE XXXI Analogous Cmpd. to MS ES Originating# Structure procedure (m + 1) from 3050

AAA 299 3026 3051

AAA 313.3 3025 3052

AAA 339 3007 3053

AAA 393 3028 3001

BBB 285.3 3006

GGG 328.2 3005

[1080] Compounds 3100 to 3106 were prepared from the substitutedBoc-protected piperazines by procedures substantially similar to X.Table XXXII TABLE XXXII Analogous Originating Cmpd. to ES MS from #Structure procedure (m + 1) compound 3100

X 199.2 3050 3101

X 213.3 3051 3102

X 239 3052 3103

X 293 3053 3105

X 185.2 3001 3106

X 228.1 3006

[1081] Compounds 3000, 3001, 3105 and 3006 were prepared from theappropriate substituted piperazines using procedures substantiallysimilar to Z. TABLE XXXIII Analogous B-C Cmpd. to ES MS OriginatingDomain # Structure procedure (m + 1) from used 3150

Z 639.4 3100 BC2 3151

Z 653.4 3101 BC2 3152

Z 625.3 3105 BC2 3153

Z 668.3 3006 BC2

[1082] Compounds 3000 and 3202 were prepared from the appropriatelysubstituted piperazines using procedures substantially similar toprocedure III. TABLE XXXIV Analogous B-C Cmpd. to ES MS OriginatingDomain # Structure procedure (m + 1) from used 3200

III 580 3102 BC2 3202

III 633 3103 BC2

[1083] Compounds 3250 to 3253 were prepared from the Boc-protectedprecursor by procedures substantially similar to procedure AA. TABLEXXXV Analogous Cmpd. to ES MS Originating # Structure procedure (m + 1)from 3250

AA 539.3 3150 3251

AA 553.2 3151 3252

AA 525.3 3152 3253

AA 568.3 3153

Preparation G1

[1084]

[1085] To 2-fluorophenylacetic ester (5.3 g, 31.5 mmol), in CCl₄ (30mL), was added N-bromosuccinimide (6.17 g, 34.6 mmol) and a catalyticamount of 2,2′-azobisisobutyronitrile. The mixture was heated at refluxfor 12 h and then allowed to cool to room temperature. The resultingprecipitate was removed by filtration and the filtrate concentrated todryness. The desired product was purified by flash chromatography (SiO₂,eluting with 10% EtOAc in Hexanes).

[1086] Yield: 7.52 g, 97%. EIS-MS 248.1 [M+1].

Preparation G2

[1087]

[1088] To compound of preparation G1 (7.52 g, 30.4 mmol), in DCM (60mL), was added TEA (8.5 mL, 60.8 mmol) and N-Boc piperazine (5.67 g,30.4 mmol) and the mixture stirred at room temperature for 12 h. Afterconcentrating to dryness, the resulting residue was taken up in EtOAc(100 mL), the organics washed with H₂O, brine, and concentrated todryness. The resulting residue was purified by flash chromatography(SiO2, eluting with 10% EtOAc in Hexanes).

[1089] Yield: 10.2 g, 95%. EIS-MS 353.2 [M+1].

Preparation G3

[1090]

[1091] To compound of preparation G2 (1.57 g. 4.45 mmol), in EtOH (20mL) and H₂O (2 mL), was added NaOH (4.45 g, 113.3 mmol). The mixture wasstirred at room temperature for 6 h and the concentrated to dryness. Theresulting acid salt was taken up in H₂O, washed with Et₂O, and theaqueous layer made slightly acidic (pH 4-5) by the cautious addition of5N HCl. The desired acid was extracted into EtOAc and the organicswashed with-brine and concentrated to dryness. Yield: 1.2 g, 80%. EIS-MS339.2 [M+1].

Preparation G4

[1092]

[1093] To compound of preparation G3 (1.11 g, 3.28 mmol), in DMF (10mL), was added diethylcyanophosphonate (0.55 mL, 3.6 mmol), diethylamine(0.40 mL, 3.94 mmol), and TEA (0.55 mL, 3.94 mmol). The mixture wasstirred at room temperature for 3 h and the diluted with EtOAc (100 mL).The organics were washed with saturated NaHCO₃, H₂O, brine, andconcentrated to dryness. Yield: 1.25 g, 97%.

[1094] EIS-MS 394.3 [M+1].

Preparation G5

[1095]

[1096] To compound of preparation G4 (0.698 g, 1.77 mmol), in CH₂Cl₂ (5mL), was added TFA (5 mL) and the mixture stirred at room temperaturefor 45 minutes. After concentrating to dryness, the resulting residuewas taken up with 1N NaOH and the desired “free” amine extracted intoEtOAc (50 mL). The organic extracts were concentrated to dryness. Yield:508 mg, 98%. EIS-MS 294.2 [M+1].

Preparation G6

[1097]

[1098] The compound of preparation G6 was prepared from2,4-difluorophenyl acetic ester by following substantially similarprocedures described in preparations 1-5. EIS-MS 312.2 [M+1].

EXAMPLE G1

[1099]

[1100] To compound of preparation G5 (0.344 g, 1.17 mmol) in DCM (10mL), was added was added compound of preparation BC2 (isomer 2, 0.538 g,1.17 mmol), DIPEA (1 mL, 5.87 mmol), and HATU (0.446 g, 1.17 mmol). Themixture was stirred at room temperature overnight and then concentratedto dryness., The resulting residue was taken up in EtOAc (50 mL), theorganics washed with saturated NaHCO₃, H₂O, brine, and concentrated todryness. The desired product was purified by flash chromatography (SiO₂,eluting with EtOAc). Yield: 0.654 g, 74%. EIS-MS 734.1 [M+1].

EXAMPLE G2

[1101]

[1102] To compound of Example G1 (0.654 g, 0.891 mmol), in DCM (10 mL),was added TFA (5 mL) and the mixture stirred at room temperature for 45minutes. After concentrating to dryness, the resulting residue wastriturated with Et₂O, the resulting solid collected by filtration anddried.

[1103] Yield: 0.540 g, 85%. EIS-MS 634.3 [M+1].

EXAMPLE G3

[1104]

[1105] To compound of preparation G6 (0.298 g, 0.958 mmol) in DCM (10mL), was added was added compound of preparation BC2 (isomer 2, 0.439 g,0.958 mmol), DIPEA (0.83 mL, 4.79 mmol), and HATU (0.364 g, 0.958 mmol).The mixture was stirred at room temperature overnight and thenconcentrated to dryness. The resulting residue was taken up in EtOAc (50mL), the organics washed with saturated NaHCO₃, H₂O, brine, andconcentrated to dryness. The desired product was purified by flashchromatography (SiO₂, eluting with EtOAc). Yield: 0.637 g, 89%. EIS-MS752.2 [M+1].

EXAMPLE G4

[1106]

[1107] To compound of Example G3 (0.635 g, 0.845 mmol), in DCM (10 mL),was added TFA (5 ml) and the mixture stirred at room temperature for 45minutes. After concentrating to dryness, the resulting residue wastriturated with Et₂O, the resulting solid collected by filtration anddried.

[1108] Yield: 669 mg, 90%. MS (ES) 652.2 [M+1].

EXAMPLE G5

[1109]

[1110] To compound of preparation G5 (0.047 g, 0.16 mmol), in DCM (4 mL)and DMF (1 rnL), was added preparation BC1 (0.08 g, 0.176 mmol), DIPEA(0.14 mL, 0.80 mmol), and HATU (0.061 g, 0.16 mmol). The mixture wasstirred at room temperature overnight and then concentrated to dryness.The resulting residue was taken up in EtOAc (50 mL), the organics washedwith saturated NaHCO₃, H₂O, brine, and concentrated to dryness. Thedesired product was purified by flash chromatography (SiO₂, eluting with20% EtOAc in Hexanes). Yield: 0.100 g, 85%. MS (ES) NA [M+1].

EXAMPLE G6

[1111]

[1112] To the compound of Example 5 (0.10 g, 0.136 mmol), in DCM (10mL), was added TFA (5 mL) and the mixture stirred at room temperaturefor 30 minutes. After concentrating to dryness, the resulting residuewas triturated with Et₂O, the resulting solid collected by filtrationand dried.

[1113] Yield: 65 mg, 55%. EIS-MS NA [M+1].

Preparation G7

[1114]

[1115] To compound of preparation G6 (0.30 g, 1.09 mmol) was addedN-Boc-4-Cl-D-Phe (0.325 g, 1.09 mmol), EDC (0.209 g, 1.09 mmol), HOBT(0.171 g, 1.09 mmol), and DCM (10 mL). The mixture was stirred at roomtemperature for 1 h and then diluted with EtOAc (50 mL). The,organicswere washed with saturated NaHCO₃, H₂O, brine, and concentrated todryness. The resulting residue was purified by flash chromatography(SiO2, eluting with 25% EtOAc in Hexanes).

[1116] Yield: 308 mg, 48%. EIS-MS 593.2 [M+1].

Preparation G8

[1117]

[1118] To compound of preparation G7 (0.698 g, 1.77 mmol), in DCM (5mL), was added TFA (5 mL) and the mixture stirred at room temperaturefor 45 minutes. After concentrating to dryness, the resulting residuewas taken up with 1N NaOH and the desired “free” amine extracted intoEtOAc (50 mL). The organic extracts were concentrated to dryness. Yield:508 mg, 98%. EIS-MS 294.2 [M+1].

Example G7

[1119]

[1120] To compound of Preparation G8 (0.196 g, 0.398 mmol) was addedisoquinoline 3-carboxylic acid (0.076 g, 0.398 ammol), EDC (0.077 g,0.398 mmol), HOBT (0.062 g, 0.398 mmol), and DCM (10 mL). The mixturewas stirred at room temperature for 1 h and then diluted with EtOAc (50mL). The organics were washed with saturated NaHCO₃, H₂O, brine, andconcentrated to dryness. The resulting residue was purified by flashchromatography (SiO2, eluting with 5% MeOH in EtOAc). Yield: 253 mg,98%.

[1121] EIS-MS 648.3 [M+1].

Preparation G9

[1122]

[1123] The compound of Preparation G9 was prepared from2,4-difluorophenyl acetic ester following substantially similarprocedures described in preparation G1-G5. EIS-MS 326.2 [M+1].

EXAMPLE G8

[1124]

[1125] To the compound of Preparation G9 (0.252 g, 0.775 mmol), in DCM(4 mL)/DMF (1 mL), was added was added compound of Preparation BC2(isomer 2, 0.355 g, 0.775 mmol), DIPEA (1.35 mL, 7.75 mmol), and HATU(0.295 g, 0.775 mmol). The mixture was stirred at room temperatureovernight and then concentrated to dryness. The resulting residue wastaken up in EtOAc (50 mL), the organics washed with saturated NaHCO₃,H₂O, brine, and concentrated to dryness. The desired product waspurified by flash chromatography (SiO₂, eluting with 100% EtOAc to90:5:5, EtOAc-Et₃-N-MeOH).

[1126] Yield: 0.438 g, 74%. EIS-MS 766.3 [M+1].

EXAMPLE G9

[1127]

[1128] To the compound of Example G8 (0.438 g, 0.572 mmol), in DCM (10mL), was added TFA (5 mL) and the mixture stirred at room temperaturefor 45 minutes. After concentrating to dryness, the resulting residuewas triturated with Et₂O, the resulting solid collected by filtrationand dried. Yield: 388 mg, 96%. EIS-MS 666.3 [M+1].

Preparation G10

[1129]

[1130] To the compound of Preparation G4 (0.407 g, 1.03 mmol), in THF(15 mL) at −78° C. was added lithium diisopropylamide (2 M, 1.3 mL, 2.58mmol) such that the temperature was <−70° C. Upon completion ofaddition, the mixture was stirred for 1 h at −78° C. and theniodomethane (0.13 mL, 2.06 mmol, which was passed through a short columnof basic alumina) was added. The mixture was allowed to warm to roomtemperature over a period of 30 minutes, and then diluted with EtOAc(100 mL). The organics were washed with saturated NaHCO₃, H₂O, brine,and concentrated to dryness. The resulting residue was purified by flashchromatography (SiO₂, eluting with 30% EtOAc in Hexanes).

[1131] Yield: 220 mg, 52%. EIS-MS 408.3 [M+1].

Preparation G11

[1132]

[1133] To the compound of Preparation G10 (0.220 g, 0.539 mmol), in DCM(10 mL), was added TFA (5 mL) and the mixture stirred at roomtemperature for 45 minutes. After concentrating to dryness, theresulting residue was taken up with 1N NaOH and the desired “free” amineextracted into EtOAc (50 mL). The organic extracts were concentrated todryness. Yield: 137 mg, 83%. EIS-MS 308.2 [M+1].

EXAMPLE G10

[1134]

[1135] To the compound of Preparation G11 (0.136 g, 0.442 mmol), in DCM(10 mL), was added preparation BC2 (isomer 2, 0.203 g, 0.442 mmol),DIPEA (0.38 mL, 2.21 mmol), and HATU (0.168 g, 0.442 mmol). The mixturewas stirred at room temperature overnight and then concentrated todryness. The resulting residue was taken up in EtOAc (50 mL), theorganics washed with saturated NaHCO₃, H₂O, brine, and concentrated todryness. The desired product was purified by flash chromatography (SiO₂,eluting with 100% EtOAc). Yield: 0.310 g, 94%. EIS-MS 748.3 [M+1].

EXAMPLE G11

[1136]

[1137] To the compound of Example G10 (0.308 g, 0.411 mmol), in DCM (10mL), was added TFA (5 mL) and the mixture stirred at room temperaturefor 45 minutes. After concentrating to dryness, the resulting residuewas triturated with Et₂O, the resulting solid collected by filtrationand dried. Yield: 324 mg, 90%. EIS-MS 648.3 [M+1].

Preparation G12

[1138]

[1139] The enantiomers of Preparation G4 (5.25 g) were separated bychiral chromatography, using a Chiralpak AD (4.6×250 mm) column, elutingwith 7% IPA, 93% heptane containing 0.2% DMEA at 1 mL/min. The firsteluting isomer was labeled isomer #1 (2.49 g) and the second elutingisomer #2 (2.34 g).

Preparation G13

[1140]

[1141] To isomer 1 of the compound of preparation G12 (2.49 g, 6.33mmol), in DCM (20 mL), was added TFA (10 mL) and the mixture stirred atroom temperature for 45 minutes. After concentrating to dryness, theresulting residue was taken up with 1N NaOH and the desired “free” amineextracted into EtOAc (50 mL). The organic extracts were concentrated todryness. Yield: 1.55 g, 83%. EIS-MS 294.2 [M+1].

Preparation G14

[1142]

[1143] To isomer 2 of the compound of preparation G12 (2.34 g, 5.95mmol), in DCM (20 mL), was added TFA (10 mL) and the mixture stirred atroom temperature for 45 minutes. After concentrating to dryness, theresulting residue was taken up with LN NaOH and the desired “free” amineextracted into EtOAc (50 mL). The organic extracts were concentrated todryness. Yield: 1.66 g, 95%. EIS-MS 294.2 [M+1].

EXAMPLES G12-G13

[1144] The compounds of examples G12-G13 were prepared from theappropriate A domain and the compound of Preparation BC2 (isomer 2) byfollowing procedures substantially similar to those described inExamples G10-G11.

Example Z MS (ES) [M + H] G12

634.3 G13

634.3

Preparation G15

[1145]

[1146] To the ester, whose preparation is described in Preparation G2,(4.68 g, 14.88 mmol), was added EtOH (25 mL), H₂O (5 mL), and NaOH (2.97g, 74.4 mmol). The mixture was stirred at room temperature overnight andthen an additional 20 equivalents of NaOH was added. The mixture wasallowed to stir for 24 h more then concentrated to dryness. Theresulting residue was taken up in H₂O, washed with EtOAc, and theaqueous layer made slightly acidic with 5N HCl (pH 5-6). The desiredacid was extracted into EtOAc. The organics were washed with brine andconcentrated to dryness. Yield: 1.6 g, 38%.

[1147] EIS-MS 287.2 [M+1].

Preparation G16

[1148]

[1149] To the compound of Preparation G15 (1.59 g, 5.55 mmol), in DMF(10 mL), was added diethylcyanophosphonate (0.84 mL, 5.55 mmol),diethylamine (0.69 mL, 6.66 mmol), and TEA (0.93 mL, 6.66 mmol) and themixture stirred at room temperature for 12 h. After diluting with EtOAc(10 fold), the organics were washed with 1N NaOH, H₂O, brine, andconcentrated to dryness. The desired product was purified by flashchromatography (SiO₂, eluting with 30% EtOAc in Hexanes). Yield: 1.51 g,80%. EIS-MS 342.3 [M+1].

Preparation G17

[1150]

[1151] To the compound of Preparation G16 (0.55 g, 1.61 mmol), in DCM(10 mL), was added TFA (5 mL) and the mixture stirred at roomtemperature for 45 minutes. After concentrating to dryness, theresulting residue was taken up in 1N NaOH, the desired amine extractedinto EtOAc, the organics washed with H₂O, brine, and concentrated todryness. Yield: quantitative. EIS-MS 242.2 [M+1].

EXAMPLE G14

[1152]

[1153] The above titled compound was prepared from the compound ofPreparation G17 (0.281 g, 1.16 mmol) and the compound of Preparation BC1by following a procedure substantially similar to that described inExample G5. Yield: 670 mg, 85%. EIS-MS 683.4 [M+1].

EXAMPLE G15

[1154]

[1155] To the compound of Example G14 (0.665 g, 0.97 mmol), in DCM (10mL), was added TFA (SrL) and the mixture stirred at room temperature for45 minutes. After concentrating to dryness, the resulting residue waspurified by reverse phase HPLC (Waters Symmetry C18 column, eluting with0.05% HCL in H₂O/CH₃CN, 90:10 to 60:40, following a straight linegradient). Yield: 540 mg, 85%. EIS-MS 582.3 [M+1].

Preparation G18

[1156]

[1157] To a solution of LiHMDS (1.0M in THF, 24 mL, 24 mmol), in THF(30mL) at −78° C. was added methyl-4-methylvalerate (2.5 g, 19.2 mmol),in THF (10 mL). The mixture was stirred for 30 minutes at −78° C. andthen transferred, via a cannula needle, to a solution of bromine (1.18mL, 23.04 mmol), in THF (2OmL) at −78° C., and the resulting mixtureallowed to warm to room temperature (30 minutes). After quenching withpH 7 buffer (20 mL), the organics were washed with saturated sodiummetabisulfite solution and concentrated to dryness. The crude materialwas taken on without any additional purification.

Preparation G19

[1158]

[1159] To the compound of Preparation G18 (19.2 mmol) was addedN-Boc-piperazine (3.57 g, 19.2 mmol), K₂CO₃ (5.3 g, 38.4 mmol), andCH₃CN (20 mL) and the mixture heated at reflux for 4 h. After cooling toroom temperature, the mixture was diluted 10 fold with EtOAc, theorganics washed with H₂O and concentrated to dryness. The resultingresidue was purified by flash chromatography (SiO₂, eluting with 15%EtOAc in Hexanes). Yield: 1.41 g, 23%. EIS-MS 315.2 [M+1].

Preparation G20

[1160]

[1161] To the compound of Preparation G19 (1.41 g, 4.49 mmol), inEtOH/H₂O (10:1, 11 mL), was added NaOH (1.79 g, 44.9 mmol) and themixture stirred at room temperature for 2 h. After concentrating todryness, the resulting residue taken up in H₂O, washed with Et₂O, andthen the aqueous layer made slightly acidic (pH 4-6) with 5N HCl. Thedesired acid was extracted into EtOAc and the organics concentrated todryness. Yield: 1.05 g, 78%. EIS-MS 301.2 [M+1].

Preparation G21

[1162]

[1163] To the compound of Preparation G20 (1.03 g, 3.42 mmol), in DMF(10 mL), was added diethylcyanophosphonate (0.57 mL, 3.77 mmol),diethylamine (0.42 mL, 4.11 mmol), and TEA (0.57 mL, 4.11 mmol) and themixture stirred at room temperature for 24 h. After diluting with EtOAc(10 fold), the organics were washed with lN NaOH, H₂O, brine, andconcentrated to dryness. The desired product was purified by flashchromatography (SiO₂, eluting with 1:1 EtOAc/Hexanes). Yield: 0.9 g,74%. EIS-MS 356.3 [M+1].

Preparation G22

[1164]

[1165] To the compound of Preparation G21 (0.9 g, 2.53 mmol), in DCM (10mL), was added TFA (5 mL) and the mixture stirred at room temperaturefor 45 minutes. After concentrating to dryness, the resulting residuewas taken up in 1N NaOH, the desired amine extracted into EtOAc, theorganics washed with H₂O, brine, and concentrated to dryness. Yield: 485mg, 75%. ESI-MS 256.2 [M+1].

EXAMPLE G16

[1166]

[1167] The compound of Example G16 was prepared from the compound ofPreparation G22 (0.193 g, 0.755 mmol) and preparation BC2 (isomer 2,0.346 g, 0.755 mmol), by following a procedure substantially similar tothat described in Preparation G14. Yield: 420 mg, 80%. EIS-MS 696.3[M+1].

EXAMPLE G17

[1168]

[1169] To the compound of Example G16 (0.420 g, 0.603 mmol), in DCM (10mL), was added TFA (5 mL) and the mixture stirred at room temperaturefor 45 minutes. After concentrating to dryness the resulting residue waspurified by reverse phase HPLC (Waters Symmetry C18 column, eluting with0.05% HCL in H₂0/CH₃CN, 90:10 to 60:40 following a straight-linegradient). Yield: 362 mg, 90%. EIS-MS 596.3 [M+1].

Preparation G23

[1170]

[1171] A mixture of cyclohexylacetic acid (25.0 g, 175.8 mmol) and SOCl₂(51.3 mL, 703.2 mmol), in CCl₄ (25 mL), was heated at 65° C. for 30minutes. Then, a suspension of NBS (37.5 g, 211.0 mmol) in CCl₄ (100 mL)was added, followed by addition of HBr (48%) (15 drops). The reactionwas heated at 85° C. for 2 h and then cooled down to room temperature.The mixture was poured carefully onto cold MeOH (400 mL) and stirred for15 minutes. Volatiles were evaporated under reduced pressure and theresidue was taken into EtOAc. The resulting solution was washed with H₂Oand brine, dried (Na₂SO₄) and concentrated to dryness. The resultingresidue was purified by flash chromatography (SiO₂, eluting withhexane-EtOAc, 30:1) to give the α-bromoester (95%) as a pale yellow oil.EIS-MS 235.1 [M⁺+1].

Preparation G24

[1172]

[1173] To the compound of Preparation G23 (25.0 g, 106.3 mmol), inanhydrous CH₃CN (500 mL), was added K₂CO₃ (29.3 g, 212.0 mmol),N-Boc-piperazine (20.8 g, 111.6 mmol), and a catalytic amount of nBu₄NI(7.85 g, 21.3 mmol). The mixture was heated under reflux for 48 h andthen cooled to room temperature. The reaction was diluted with EtOAc,washed with H₂O, brine, dried (Na₂SO₄), and concentrated to dryness. Theresulting residue was purified by flash chromatography (SiO₂, elutingwith hexane-EtOAc, 9:1) to afford the title compound (34%) as a whitesolid. EIS-MS 341.2 [M⁺+1].

Preparation G25

[1174]

[1175] To the compound of Preparation G24 (1.0 g, 3.21 mmol), in acetone(22 mL) at 0° C., Jones reagent (5.6 mL) was added. The reaction mixturewas allowed to react at 0° C. for 1 h and then 2.5 h at roomtemperature. Then, H₂O (20 mL) and isopropanol (20 mL) were added, andthe pH adjusted to 67 with the addition of 1N KOH. The aqueous solutionwas extracted with EtOAc (4×) and the combined organic layers dried(MgSO₄) and concentrated to dryness; affording the title compound (70%)as a solid. EIS-MS 326.7 [M++1].

Preparation G26

[1176]

[1177] To the compound of Preparation G25 (300 mg, 0.92 mmol), in DCM(4.8 mL) and DMF (1 mL) at room temperature, diisopropylethyl amine (0.8mL, 4.6 mmol), diethylamine (0.114 mL, 1.10 mmol) and HOBT (155 mg, 1.15mmol) were added and the mixture stirred for 5 minutes. Then, EDC (220mg, 1.15 mmol) was added and the reaction stirred overnight at roomtemperature. Then, H₂O (10 mL) was added and mixture diluted with DCM(10 mL). The layers were separated and the aqueous phase was extractedwith DCM. The combined organic layers were dried (MgSO₄) andconcentrated to dryness. The resulting residue was purified by flashchromatography (SiO₂, eluting with hexane/EtOAc, 7:3) to afford theN-Boc protected amide as an oil. A solution of the N-Boc derivative (203mg, 0.53 mmol) in 1N HCl/EtOAc (20 mL) was stirred at room temperatureovernight. After concentrating to dryness, the resulting solid waswashed twice with Et₂O to afford the title compound (58%) as a whitesolid. EIS-MS 281.9 [M⁺+1].

Preparation G27

[1178]

[1179] Following the general procedure described in Preparation G26,andlusing pyrrolidine and the compound of Preparation G25 as startingmaterials, the title compound was prepared .(40%) . EIS-MS 279.8 [M++1].

EXAMPLES G18-G19

[1180] The compounds of Examples G18-G19 were prepared from theappropriate A domain and the compound of Preparation BC2 by followingsubstantially similar procedures described in Examples G3-G4.

Example Z ESI-MS [M + 1] G18

622.4 G19

620.4

Preparation G27.5

[1181]

[1182]3-[2-(4-Chloro-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

[1183] A. To a 0° C. solution of 4-Cl-D-Phe methyl ester (23.8 g, 111.0mmol), Boc-D-Tic (30.8 g, 111.0 mmol) and 4-DMAP (75 mg, 0.61 mmol) in200 mL of DCM was added EDC (30.8 g, 111.0 mmol) and the mixture stirredfor 20 minutes. The ice bath was removed and the mixture stirred at roomtemperature for 4 h. After washing with water (4×200 mL), the combinedaqueous portions were back extracted with DCM (2×200 mL). The combinedorganic portions were washed with brine, dried (MgSO₄), and concentratedto dryness. The desired product was purified by flash chromatography(SiO₂, eluting with 35% EtOAc in Hexanes) affording 43.0 g (83%) of theester. EIS MS 473 [M+1].

[1184] B. To the above formed ester (43.0 g, 91.0 mmol), in MeOH (170mL) at 0° C., was added lN NaOH (227.0 mL, 227.0 mmol), dropwise. After20 minutes the ice bath was removed and the mixture stirred at roomtemperature for 3 h. The mixture was concentrated to dryness, and theresulting residue suspended in 200 mL of water. The aqueous layer wasmade acidic (pH 1) with 5 N hydrochloric acid and extracted with EtOAc(4×200 mL). The combined organics were dried (MgSO₄), filtered, andconcentrated to dryness; affording 39.0 g (93%) of the title compound.EIS-MS 459 [M+1].

Preparation G28

[1185]

[1186]1-{[1-Carboxy-2-(4-chloro-phenyl)-ethylcarbamoyl]-methyl}-1,3-dihydro-isoindole-2-carboxylicacid tert-butyl ester

[1187] A. To a suspension of 4-Cl-D-Phe methyl ester hydrochloride (40.4g, 161.5 mmol), in DCM (250 mL), was added saturated aqueous sodiumbicarbonate (250 mL) and the mixture stirred at room temperature for 1h. The organic portion was separated and the aqueous portion wasextracted with DCM (2×). The combined organic portions were dried(Na₂SO₄) and concentrated to dryness. To the free amine, in DCM (400 mL)at 0° C., was added example 82 (isomer 2, 44.8 g, 161.5 mmol), EDC (31.0g, 161.5 mmol) and 4-DMAP (2.0 g, 16.1 mmol). The reaction mixture wasstirred at 0° C. for 30 minutes whereupon the cooling bath was removedand the reaction mixture was stirred for another 5 h at roomtemperature. The mixture was then washed with saturated aqueous sodiumbicarbonate (200 mL), 10% aqueous sodium bisulfate (200 mL), dried(Na₂SO₄), and concentrated to dryness to afford 76.4 g (100%) of theester. EIS-MS 471 [M−1].

[1188] B. To the ester from Part A (76.4 g, 161.5 mmol), in MeOH (760mL), was added 1 N NaOH (242.0 mL, 242.0 mmol) and the mixture heated at50° C. for 4 h. then stirred for another 16 h at room temperature. Afterconcentrating to dryness, the resulting residue was taken up in 500 mLof water and washed with diethyl ether (2×). The aqueous portion wasacidified to pH 2 with 10% aqueous sodium bisulfate and extracted withEtOAc (4×200 mL). The combined organic extracts were dried (MgSO₄) andconcentrated to dryness. The resulting solid was suspended in hexanes,filtered, and dried to afford 67.7 g (91%) of the title compound.

[1189] EIS-MS 457 [M−1].

Preparation of Sulfonated Derivatives and More Preparation SM 1

[1190]

[1191] 1-Methoxycarbonybnethyl-1,3-dihydro-isoindole-2-carboxylic acidtert-butyl ester

[1192] A. (2-Bromo-benzyl)-carbamic acid tert-butyl ester: To a mixtureof 125.0 g (561.8 mmol) of 2-bromobenzylamine hydrochloride and 170.7 g(1236.0 mmol) of potassium carbonate in 300 mL of 50%tetrahydrofuran/water was added 134.9 g (618.0 mmol) of di-tert-butyldicarbonate in four portions over 20 min. The mixture was stirred atroom temperature for 16 hr. and diluted with 300 mL of ethyl acetate and300 mL of water. The organic portion was separated and the aqueousportion was extracted three times with 200 mL each of ethyl acetate. Thecombined ethyl acetate portions were washed once with 250 mL of 10%aqueous sodium bisulfate. The organic portion was dried (MgSO4),filtered and concentrated in vacuo to afford 161.0 g of the titlecompound.

[1193] B. 3-[2-(tert-Butoxycarbonylamino-methyl)-phenyl]-acrylic acidmethyl ester: To a solution of 161.0 g (561.8 mmol) of material fromPart A, 58.0 g (674.2 mmol) of methyl acrylate and 170.5 g (1685.4 mmol)of triethylamine in 800 mL of N,N-dimethylformamide was added 7.9 g(11.2 mmol) of dichlorobis(triphenylphosphine)palladium(II) and themixture was heated at 80° C. for 32 hr. The mixture was cooled, dilutedwith 1000 mL of ethyl acetate and washed with 10% aqueous sodiumbisulfate. The aqueous portion was extracted three times with ethylacetate and the combined organics were dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was dissolved in a small amount ofdichloromethane and filtered through 7 in. of silica gel in a 2 Lsintered glass funnel eluting with 25% ethyl acetate/hexanes. The eluantwas concentrated in vacuo and recrystallized from ethyl acetate/hexanesto afford 116.9 g (71%) of the title compound.

[1194] C. To a 0° C. solution of 116.9 g (401.2 mmol) of material fromPart B in 800 mL of dichloromethane was added 200 mL of trifluoroaceticacid dropwise over 15 min. After removing the cooling bath, the mixturewas stirred for 2.5 hr. and concentrated in vacuo. The residue wasdissolved in 500 mL of dichlorormethane and saturated aqueous sodiumbicarbonate was slowly added until the mixture was slightly basic. Theorganic portion was separated and the aqueous portion was extracted twotimes with dichloromethane. The combined organic portions were dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was dissolvedin 800 mL of dichloromethane and 57.0 g (441.4 mmol) ofN,N-diisopropylethylamine was added. To the mixture was added 96.3 g(441.4 mmol) of di-tert-butyl dicarbonate in five portions over 45 min.and the mixture was stirred at room temperature for 16 hr. The mixturewas washed with 10% aqueous sodium bisulfate. The organic portion wasseparated and the aqueous portion was extracted two times withdichloromethane. The combined organics were dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was dissolved in a small amount ofdichloromethane and filtered through 7 in. of silica gel in a 2 Lsintered glass funnel eluting with 25% ethyl acetate/hexanes. The eluantwas concentrated in vacuo and chiral chromatography of the residue(Chiralcel OD) afforded 52.6 g (45%) of the title compound.

[1195] Mass Spectrum: M+1=292.

Preparation SM2

[1196]

[1197] 1-Carboxymethyl-1,3-dihydroisoindole-2-carboxyhc acid tert-butylester

[1198] To a solution of 52.6 g (180.5 mmol) of material from PreprationSM1 in 500 mL of methyl alcohol was added 199.0 mL (199.0 mmol) of 1 Nsodium hydroxide. The mixture was stirred at room temperature for 48 hr.and concentrated in vacuo. The residue was dissolved in 300 mL of waterand extracted two times with diethyl ether. The aqueous portion wasacidified to pH 2 with 10% aqueous sodium bisulfate and extracted fourtimes with ethyl acetate. The combined ethyl acetate portions were dried(MgSO₄), filtered and concentrated in vacuo. The residue was suspendedin diethyl ether and concentrated in vacuo two times to afford 49.8 g(99%) of the title compound.

[1199] Mass Spectrum: M-1=276.

Preparation SM3

[1200]

[1201]3-[1-Carboxy-2-(4-chloro-phenyl)-ethylcarbamoyl]-3,4-dihydro-1H-isoqumoline-2-carboxylicacid tert-butyl ester

[1202] A.3-[2-(4-Chloro-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester: To a 0° C. solution of D-4chlorophenylalaninemethyl ester (23.8 g, 111.0 mmol), Boc-D-1,2,3,4-tetrahydroisoquinolinecarboxylic acid (30.8 g,111.0) and 4-dimethylaminopyridine (75 mg, 0.61mmol) in 200 mL of dichloromethane is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 30.8 g,111.0 mmol) and the mixture stirred for 20 min. Remove ice bath and stirat room temperature for 4 hr. Wash 4 times with 200 mL each of water.The combined aqueous portions are extracted two times with 200 mL ofdichloromethane. The combined organic portions are washed once withbrine, dried (MgSO₄), filtered and concentrated in vacuo. Chromatography(silica gel, 35% ethyl acetate/hexanes) of the residue affords 43.0 g(83%) of the title compound.

[1203] Elecrospray Mass Spectrum: M+1=473.

[1204] B. To a 0° C. solution of material from part A (43.0 g, 91.0mmol) in 170 mL of methanol was added dropwise 1N, sodium hydroxide(227.0 mL, 227.0 mmol). After 20 min the ice bath is removed and themixture is stirred at room temperature for 3 hr. The mixture isconcentrated in vacuo, and the residue is suspended in 200 mL of water.Adjust to pH 1 with 5 N hydrochloric acid and extract aqueous four timeswith 200 mL each of ethyl acetate. The combined organics are dried(MgSO₄), filtered and concentrated in vacuo to afford 39.0 g (93%) ofthe title compound.

[1205] Elecrospray Mass Spectrum: M+1=459.

EXAMPLE S1

[1206]

[1207] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid[2-{4-[2-acetylamino-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-1-(4-chloro-benzyl)-2-oxo-ethyl]-amidehydrochloride

[1208] A.4-[2-Acetylamino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester: To a solution of 0.25 g (0.77 mmol) of4-[2-Amino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester and 0.12 mL (0.85 tmol) of triethylamine in 3 mL ofdichloromethane is slowly added 0.06 mL (0.85 mmol) of acetyl chloride.After one hr, saturated sodium bicarbonate is added and the organicportion is separated. The aqueous portion is diluted with 3 mL of 1Nsodium hydroxide and extracted four times with dichloromethane. Thecombined organics are dried (Na₂SO₄), filtered and concentrated in vacuoto afford 0.28 g (100%) of the title compound.

[1209] B. N-[2-(2-Fluoro-phenyl)-2-piperazin-1-yl-ethyllacetamide: To asolution of 0.28 g (0.77 mmol) of material from part A in 1 mL ofdichloromethane is added 1 mL of trifluoroacetic acid. After stirringfor one hr, the mixture is concentrated in vacuo. The residue ispartitioned between 1N sodium hydroxide and dichloromethane. The organicportion is separated and the aqueous portion is extracted three timeswith dichloromethane. The combined organics are dried (Na₂SO₄), filteredand concentrated in vacuo to afford 0.15 g (73%) of the title compound.

[1210] C.3-[2-{4-[2-Acetylamino-1-(2-fluoro-phenyl)ethyl]-piperazin-1-yl}-1-(4-chloro-benzyl)-2-oxo-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester: To a mixture of 0.28 g (0.62 mmol) of productfrom Preparation SM3, 0.15 g (0.57 mmol) of material from part B and0.24 g (0.62 mmol) ofO-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate in 2 ml of dichlorormethane is added 0.11 mL (0.62mmol) of N,N-diisopropylethylamine. The mixture is stirred for three hrand washed with 10% aqueous sodium bisulfate. After the organic portionis separated, the aqueous portion is saturated with sodium chloride andextracted three times with dichloromethane. The combined organics aredried (Na₂SO₄), filtered and concentrated in vacuo. Chromatography(Biotage, 5% ethanol, ethyl acetate) afforded 0.23 g (52%) of the titlecompound.

[1211] D. To a solution of 0.22 g (0.31 mmol) of material from part C in1 mL of dichloromethane is added 0.5 mL of trifluoroacetic acid. Afterstirring for 1 hr, the mixture is concentrated in vacuo. The residue isdissolved in 5 mL of 1N hydrochloric acid and lyophilized. The resultingsolid is subjected to reverse phase preparative HPLC and concentrated invacuo. The residue is dissolved in 2 mL of 1 N hydrochloric acid andlyophilized to afford 89 mg (45%) of the title compound. ElectrosprayMass Spectrum: M+1=606.

EXAMPLE S2

[1212]

[1213] 1,2,3,4-Tetrahydro-isoqumoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[1-(2-fluoro-phenyl)-2-propionylamino-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amidehydrochloride

[1214] A.4-[1-(2-Fluoro-phenyl)-2-propionylamino-ethyl]-piperazine-1-carboxylicacid tert-butyl ester: To a solution of 0.25 g (0.77 mmol) of4-[2-Amino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester and 0.12 mL (0.85 mmol) of triethylamine in 3 mL ofdichlorormethane is slowly added 0.07 mL (0.85 mmol) of acetyl chloride.After one hr, the mixture is diluted with 3 mL of 1N sodium hydroxideand extracted four times with dichloromethane. The combined organics aredried (Na₂SO₄), filtered and concentrated in vacuo to afford 0.29 g(99%) of the title compound.

[1215] B. N-[2-(2-Fluoro-phenyl)-2-piperazin-1-yl-ethyl]-propionamide:To a solution of 0.29 g (0.77 mmol) of material from part A in 1 mL ofdichloromethane is added 1 mL of trifluoroacetic acid. After stirringfor 30 min, the mixture is concentrated in vacuo. The residue ispartitioned between 1N sodium hydroxide and dichloromethane. The organicportion is separated and the aqueous portion is extracted three timeswith dichloromethane. The combined organics are dried (Na₂SO₄), filteredand concentrated in vacuo to afford 0.17 g (77%) of the title compound.

[1216] C.3-(1-(4-Chloro-benzyl)-2-{4-[1-(2-fluoro-phenyl)-2-propionylamino-ethyl]-piperazin-1-yl}-2-oxo-ethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester: To a mixture of 0.30 g (0.65 mmol) of the productfrom Preparation SM3, 0.17 g (0.59 mmol) of material from part B and0.25 g (0.65 mmol) of0-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate in 2 ml of dichlorormethane is added 0.11 mL (0.62mmol) of N,N-diisopropylethylamine. The mixture is stirred for three hrand washed with 10% aqueous sodium bisulfate. After the organic portionis separated, the aqueous portion is saturated with sodium chloride andextracted three times with dichloromethane. The combined organics aredried (Na₂SO₄), filtered and concentrated in vacuo. Chromatography(Biotage, 5% ethanol, ethyl acetate) of the residue affords a mixturewhich is chromatographed again (Biotage, 0.25% NH₄OH/2.25%methanol/dichloromethane) affords 0.23 g (53%) of the title compound.

[1217] D. To a solution of 0.21 g (0.29 mmol) of material from part C in1 mL of dichlorormethane is added 0.5 mL of trifluoroacetic acid. Afterstirring for 30 min, the mixture is concentrated in vacuo. The residueis dissolved in 2.5 mL of 1N hydrochloric acid and lyophilized. Theresulting solid is chromatographed (Biotage, 2% (9:1methanol:NH₄OH)/dichloromethane to 100% methanol) and concentrated invacuo. The residue is dissolved in dichloromethane, filtered throughcelite and concentrated in vacuo. The residue is dissolved in 2 mL of 1N hydrochloric acid and lyophilized to afford 73 mg (38%) of the titlecompound.

[1218] Electrospray Mass Spectrum: M+1=620.

EXAMPLE S3

[1219]

[1220] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4[1-(2-fluoro-phenyl)-2-isobutyrylamino-rthyl]-piperazin-1-yl}-2-oxo-ethyl)-amidehydrochloride

[1221] A.4-[1-(2-Fluoro-phenyl)-2-isobutyrylamino-ethyl]-piperazine-1-carboxylicacid tert-butyl ester: To a solution of 0.25 g (0.77 mmol) of4-[2-Amino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester and 012 mL (0.85 mmol) of triethylamine in 3 mL ofdichlorormethane is slowly added 0.09 mL (0.85 mmol) of acetyl chloride.After one hr, the mixture is diluted with 3 mL of 1N sodium hydroxideand extracted four times with dichloromethane. The combined organics aredried (Na₂SO₄), filtered and concentrated in vacuo to afford 0.26 g(86%) of the title compound

[1222] B. N-[2-(2-Fluoro-phenyl)-2-piperazin-1-yl-ethyl]-isobutyramide:To a solution of 0.25 g (0.64 mmol) of material from part A in 2 mL ofdichloromethane is added 1 mL of trifluoroacetic acid. After stirringfor 20 min, the mixture is concentrated in vacuo. The residue ispartitioned between 1N sodium hydroxide and dichloromethane. The organicportion is separated and the aqueous portion is extracted three timeswith dichloromethane. The combined organics are dried (Na₂SO₄), filteredand concentrated in vacuo to afford 0.15 g (60%) of the title compound.

[1223] C.3-(1-(4-Chloro-benzyl)-2-{4-[1-(2-fluoro-phenyl)-2-isobutyrylamino-ethyl]-piperazin-1-yl}-2-oxo-ethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2carboxylicacid tert-butyl ester: To a mixture of 0.26 g (0.56 mmol) of productfrom Preparation SM3, 0.15 g (0.51 mmol) of material from part B and0.21 g (0.56 mmol) ofO-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoroph6sphate in 2 ml of dichlorormethane is added 0.10 mL (0.56mmol) of N,N-diisopropylethylamine. The mixture is stirred for 16 hr andwashed with 10% aqueous sodium bisulfate. After the organic portion isseparated, the aqueous portion is saturated with sodium chloride andextracted three times with dichloromethane. The combined organics aredried (Na₂SO₄), filtered and concentrated in vacuo. Chromatography(Biotage, 5% ethanol, ethyl acetate) affords 0.17 g (42%) of the titlecompound.

[1224] D. To a solution of 0.17 g (0.23 mmol) of material from part C in1 mL, of dichlorormethane is added 0.5 mL of trifluoroacetic acid. Afterstirring for one hr, the mixture is concentrated in vacuo. The residueis dissolved in 2.5 mL of 1N hydrochloric acid and lyophilized. Theresulting solid is chromatographed (Reverse phase preparative HPLC) andconcentrated in vacuo. The residue is dissolved in 2 mL of 1 Nhydrochloric acid and lyophilized to afford 90mg (58%) of the titlecompound.

[1225] Electrospray Mass Spectrum: M+1=634.

EXAMPLE S4

[1226]

[1227]N-(1-(4-Chloro-benzyl)-2-{4-[1-cyclohexyl-2-(1,1-dioxo-1□⁶-isothiazolidin-2-yl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedihydrochloride

[1228] A. To a 0° C. solution of4-(2-Amino-1-cyclohexyl-ethyl)-piperazine-1-carboxylic acid tert-butylester and 0.15 mL (1.06 mmol) of triethylamine in 3 mL ofdichlorormethane is added 0.13 mL (1.06 mmol) of 3-chloropropanesulfonylchloride. The cooling bath is removed and the mixture is stirred for 16hr. The mixture is washed once with 10% aqueous sodium bisulfate and theorganic portion is separated. The aqueous portion is extracted threetimes with dichloromethane. The combined organics are dried (Na₂SO₄),filtered and concentrated in vacuo. Chromatography (Silica gel, 25%ethyl acetate/hexanes) of the residue affords 0.25 g (57%) of the titlecompound.

[1229] Mass Spectrum: M-1=450.

[1230] B.4-[1-Cyclohexyl-2-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-ethyl]-piperazine-1-carboxylicacid tert-butyl ester: To a solution of 0.24 g (0.53 mmol) of materialfrom part A in 2 mL of tetrahydrofuran is added 0.80 mL (0.80 mmol) of1M sodium bis(trimethylsilyl)amide in tetrahydrofuran. The mixture issrirred for 16 hr at room temperature then heated to reflux for 1 hr.The mixture is cooled, diluted with ethyl acetate and washed with water.The organic portion is separated and the aqueous portion is extractedtwice with ethyl acetate. The combined organics are dried (MgSO4),filtered and concentrated in vacuo. Chromatography (Silica gel, 60%ethyl acetate/hexane) of the residue affords 0.10 g (45%) of the titlecompound.

[1231] Mass Spectrum: M+1=416.

[1232] C.1-[1-Cyclohexyl-2-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-ethyl]-piperazine:To a solution of 0.1 Og (0.23 mmol) of material from part B in 1 mL ofdichloromethane is added 0.5 mL of trifluoroacetic acid and the mixtureis stirred for 1 hr and concentrated in vacuo. The residue ispartitioned between 1N sodium hydroxide and dichloromethane. The organicportion is separated and the aqueous portion is extracted twice withdichloromethane. The combined organics are dried (Na₂SO₄), filtered andconcentrated in vacuo to afford 76 mg (100%) of the title compound.

[1233] Mass Spectrum: M+1=328.

[1234] D.1-[(1-(4-Chloro-benzyl)-2-{4-[1-cyclohexyl-2-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-ethyl]-piperazin-1-yl}-2-oxo-ethylcarbamoyl)-methyl]-1,3-dihydro-2-carboxylicacid tert-butyl ester: To a suspension of 0.074 g (0.23 mmol) ofmaterial from part C, 0.11 g (0.23 mmol) of1-{[1-Carboxy-2-(4-chloro-phenyl)-ethylcarbamoyl]-methyl}-1,3-dihydro-isoindole-2-carboxylicacid tert-butyl ester and 0.24 g (0.62. mmol) ofO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronuimhexafluorophosphate in 2 mL of dichloromethane is added 0.11 mL (0.62mmol) of N,N-diisopropylethylamine. After 3 hr the mixture is washedonce with 10% aqueous sodium bisulfate. The organic portion is separatedand the aqueous potion is saturated by addition of sodium chloride. Theaqueous portion is extracted three times with dichloromethane. Thecombined organic portions are dried (Na₂SO₄), filtered and concentratedin vacuo. Chromatography (Silica gel, 75% ethyl acetate/hexane) of theresidue affords 0.10 g (56%) of the title compound.

[1235] Mass Spectrum: M+1=756.

[1236] E. To a solution of 0.10 g (0.13 mmol) of material from part D in1 mL of dichloromethane is added 0.5 mL of trifluoroacetic acid. After 1hr the mixture is concentrated in vacuo. Chromatography (Silica gel,0.2% ammonium hydroxide/1.8% methanol/dichloromethane) affords a solidwhich is dissolved in 5 ml of dichloromethane. To this solution is added1 mL of 2M hydrogen chloride in diethyl ether and the mixture isconcentrated in vacuo. The residue is suspended in diethyl ether,filtered and dried in vacuo to afford 70 mg (74%) of the title compound.

[1237] Mass Spectrum: M+1=656.

Preparations of Other Non-qlycinic A-Domain Preparation NA1

[1238]

[1239] 4-(1-Cyclohexyl-2-hydroxy-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

[1240] Step I: Preparation of Bromo-cyclohexyl-acetic acid

methyl ester

[1241]

Method A

[1242] A mixture of cyclohexylacetic acid (25.0 g, 175.8 mmol) and SOCl₂(51.3 mL, 703.2 mmol) in CCl₄ (25 mL) was heated at 65° C. for 30 min.Then, a suspension of NBS (37.5 g, 211.0 mmol) in CCl₄ (100 mL) wasadded, followed by addition of HBr (48%) (15 drops). Reaction was heatedat 85° C. for 2 h and then cooled down to room temperature. Mixture waspoured carefully onto cold MeOH (400 mL) and stirred for 15 min.Volatiles were evaporated under reduced pressure and the residue wastaken into EtOAc. The resulting solution was washed with H₂O and brine,dried (Na₂SO₄) and evaporated under reduced pressure. Residue waspurified by column chromatography (hexaneEtOAc 30:1) to give thea-bromoester (95%) as a pale yellow oil. MS m/z 235.1 (M⁺+1).

Method B

[1243] To a solution of methyl cyclohexylacetate (14.0 mL, 85.1 mmol) inanhydrous THF (140 mL) under nitrogen atmosphere at −78° C., a 1.0 Msolution of LiHMDS in THF (93.6 mL, 93.6 mmol) was added. Reaction wasstirred for 30 min and a solution of chlorotrimethylsilane (19.4 mL,153.2 mmol) in anhydrous THF (140 mL) was added via cannula at −78° C.After 30 min., NBS (17.6 g, 98.9 mmol) was added in one portion and thereaction mixture was allowed to react at room temperature for 3.5 h.Reaction was quenched with a saturated aqueous solution of NH₄Cl (100mL) and diluted with EtOAc (500 mL). The layers were separated and theaqueous phase was extracted with EtOAc (100 mL). The combined organiclayers was dried (MgSO₄), filtered and concentrated under reducedpressure. The residue was purified by column chromatography(hexane-EtOAc 9:1) to afford an inseparable 1:1.4 mixture of startingmaterial and α-bromoester respectively (14.6 g). MS m/z 235.1 (M⁺+1).

[1244] Step II: Preparation of4-(Cyclohexyl-methoxycarbonyl-methyl)-piperazine-1-carboxylic acidtert-butyl ester

[1245] To a solution the product of Step I (25.0 g, 106.3 mmol) inanhydrous CH₃CN (500 mL), K₂CO₃ (29.3 g, 212.0 rmnol), N-Boc-piperazine(20.8 g, 111.6 mmol), and a catalytic amount of nBu₄NI (7.85 g, 21.3mmol) were added. Mixture was heated under reflux for 48 h and thencooled to room temperature. Reaction was diluted with EtOAc, washed withH₂O and brine, dried (Na₂SO₄) and evaporated under reduced pressure. Theresidue was purified by column chromatography (hexane-EtOAc 9:1) toafford the title compound (34%) as a white solid. MS m/z 341.2 (M⁺+1).

[1246] Step III: Preparation of4-(1-Cyclobexyl-2-hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butylester

[1247] To an ice cooled solution of the product of Step II (9.75 g, 28.7mmol) in ihF (200 mL) under nitrogen, LAH (2.18 g, 57.4 mmol) was addedportionwise. Mixture was allowed to react at room temperature for 20minutes. Reaction was cooled to 0° C., and H₂O (1.6 mL) and 2N NaOH (7mL) were carefully added. The mixture was stirred for 1 h and filteredthrough a pad of silica gel and Celite. Solvent was removed underreduced pressure to afford the title compound (96%) as a white solid. MSm/z 313.2 (M⁺+1)

Preparation NA2

[1248]

[1249] 4-(1-Cyclohexyl-2-oxo-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

[1250] To a solution of oxalyl chloride (1.61 mL, 18.8 mmol) in CH₂Cl₂(150 mL) at −78° C. under nitrogen atmosphere, a solution of DMSO (2.8mL, 39.25 mmol) was added dropwise and stirred for 10 min. To thismixture, a solution of the product of Preparation NAl (4.9 g, 15.7 mmol)in CH₂Cl₂ (30 mL) was added dropwise and reaction was stirred at thesame temperature for 30 minutes. Then, Et₃N (10.9 mL, 78.5 mmol) wasadded and mixture allowed to react at room temperature. After 30 min,reaction mixture was quenched with H₂O (100 mL), the layers wereseparated and the aqueous layer was extracted with CH₂Cl₂ (2×). Thecombined organic layers were dried (Na₂SO₄), filtered and evaporated toafford the title compound (82%) as a colorless oil. MS m/z 311.4 (M⁺+1)

Preparation NA3

[1251]

[1252] 4-(Carboxy-cyclohexyl-methyl)-piperazine-1-carboxylic acidtert-butyl ester

[1253] To a solution of the product of Preparation NA1 (1.0 g, 3.21mmol) in acetone (22 mL) at 0° C., Jones reagent (5.6 EL) was added. Thereaction mixture was allowed to react at 0° C. for 1 h and 2.5 h at roomtemperature. Then, H₂O (20 mL) and isopropanol (20 mL) were added, andpH adjustedto 6-7 upon addition of 1N KOH. Resulting aqueous solutionwas extracted with EtOAc (4×) and the combined organic layers were dried(MgSO₄), filtered and concentrated under reduced pressure to afford thetitle compound (70%) as a solid. MS m/z 326.7 (M⁺+1)

Preparation NA4

[1254]

[1255]4-[(1-Cyclohexyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl)]-piperazine-1-carboxylicacid tert-butyl ester

Method A

[1256] To solution of the product of Preparation NA1 (5.0 g, 16.0 mmol),phthalimide (2.6 g, 17.6 mmol) and triphenylphosphine (4.6 g, 17.6 mmol)in anhydrous THF (80 mL) at 0° C., DEAD (2.8 mL, 17.6 mmol) was addeddropwise. The mixture was stirred for 1 h and then the solvent wasremoved under reduced pressure. The residue obtained was purified bycolumn chromatography (hexane/EtOAc 3:1) to afford the title compound(80%) as a solid. MS m/z 442.3 (M⁺+1)

Method B

[1257] Step I: Preparation of4-[(1-Cyclohexyl-2-hydroxyimino-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

[1258] A mixture of the product of Preparation NA2 (1.0 g, 3.22 mmol),hydroxylamine hydrochloride (0.27 g, 3.86 mmol) and pyridine (0.62 mL,;.72 mmol) in CH₂Cl₂ (20 mL) was stirred at room temperature for 16 h.The solvent was evaporated under reduced pressure and the residuepurified by column chromatography (hexane-EtOAc 4:1) to afford the oxime(62%) as a white solid. MS m/z 326.4 (M⁺+1).

[1259] Step II: Preparation of4-[(1-Cyclohexyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl)]-piperazine-1-carboxylic acid tert-butyl ester

[1260] To a solution of NiCl₂·6H₂O (402 mg, 1.69 mmol) in MeOH (20 rnL),NaBH₄ (64 mg, 1.69 mmol)) was added. To the resulting black solution, asolution of the product of Step I (550 mg, 1.69 mmol) in MeOH (5 mL) wasadded, followed by NaBH₄ (351 mg, 9.3 mmol) portionwise. The mixture wasstirred for 5 min and filtered through celite. The solution was dilutedwith EtOAc and washed with a 4% aqueous solution of NH₄OH, dried,filtered and evaporated to afford the primary amine. A solution of thiscrude and phthalic anhydride (243 mg, 1.64 mmol) in CHCl₃ (10 mL) washeated at 70° C. for 2 h. The solvent was evaporated and the residuepurified by column chromatography (hexane-EtOAc 5:1) to afford the titlecompound (15%) as a solid. MS m/z 442.3 (M⁺+1) Enantiomers of thisproduct were separated by chiral HPLC (CHIRALPAK AD 20 μm, 100%methanol/DMEA 0.1% isocratic mode, 1 mL/min). Isomer 1 t=8.5 min; Isomer2 t=10.4 min.

Preparation NA5

[1261]

[1262] 4-(2-Amino-1-cyclohexyl-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

Method A

[1263] A solution of the product of Preparation NA4 (3.0 g, 6.79 mmol)in a 0.2N solution hydrazine monohydrate in MeOH (0.51 L) (0.2 M) wasrefluxed for 3 hours. Solvent was removed under reduced pressure and theresidue was dissolved in CHCl₃. The insoluble materials were filteredoff and the filtrated was concentrated to dryness to afford the titlecompound (99%) as yellow oil. MS m/z 312.2 (M⁺+1). Enantiomer I wasobtained from Isomer 1 of Preparation NA4. Enantiomer II was obtainedfrom Isomer 2 of Preparation NA4.

Method B

[1264] Step I: Preparation of4-[(1-Cyclohexyl-2-nitro-ethyl)]-piperazine-1-carboxylic acid tert-butylester

[1265] To a solution of (2-nitrovinyl)-cyclohexane (2.63 g, 16.94 mmol),prepared as in J. Org. Chem. 1993, 58, 3850, in dry CH₂Cl₂ (22 mL),N-Boc piperazine (2.63 g, 14.12 mmol) was added at room temperature andreaction stirred overnight. Solvent was removed under reduced pressureto afford the adduct product (99%) as an oil. MS m/z 342.4 (M⁺+1) .

[1266] Step II: Preparation of4-[(2-amino-1-Cyclohexyl-ethyl)]-piperazine-1-carboxylic acid tert-butylester

[1267] Samarium powder 40 mesh (10.72 g, 71.3 mmol) and 1,2-diiodoethane(18.67 g, 66.24 mmol) were placed in a flame dried 1000 mL round bottomflask. The flask was purged of nitrogen by a triple evacuated fillprocess. Dry THF (100 mL) was added and the mixture was stirred for 1 h.Then, it was diluted with additional dry THF (200 mL) and stirred for 1h and 45 min. To this mixture, a solution of the Step I product (3.5 g,10.19 mmol) in anhydrous THF (60 mL) and MeOH (30 mL) was added viacannula and reaction stirred at room temperature overnight. A solutionof oxalic acid dihydrate (15.4 g, 122.3 mmol) in H₂O (125 mL) was addedto quench the reaction and the resulting suspension was diluted with H₂O(400 mL) and filtered through celite. Organic solvents were removedunder reduced pressure and the aqueous solution was neutralized withNaOH (9.78 g, 244.6 mmol) and extracted with EtOAc (3×600 mL). Thecombined organic layers were washed with brine, dried (MgSO₄), filteredand concentrated under reduced pressure. The crude was purified by a C18cartridge to afford the title compound (14%). MS m/z 312.2 (M⁺+1)

Preparation NA6

[1268]

[1269] (2-Cyclohexyl-2-piperazin-1-yl-ethyl)-diethyl-aminetrihydrochloride salt

Method A

[1270] To a solution of the product of Preparation NA2 (2.4 g, 7.73mmol) in dry 1,2-dichloroethane (75 mL), diethylamine was added at roomtemperature. Mixture was stirred for 15 min and then sodiumtriacetoxyborohydride (2.46 g, 11.6 mmol) was added. Reaction mixturewas stirred at room temperature overnight and then quenched with asaturated aqueous solution of NaHCO₃. Layers were separated and aqueousphase was extracted with EtOAc (3×). The combined organic layers weredried (MgSO₄), filtered and concentrated under reduced pressure. Residuewas purified by column chromatography (EtOAc, then EtOAc-MeOH-Et₃N90:5:5) to give the N-Boc protected product as an oil. Enantiomers ofthis N-Boc protected product could be separated by chiral HPLC(CHIRALPAK AD (4.6×250 mm), hexane-TFA 0.05%/isopropanol (9:1) isocraticmode, 1 mL/min). Isomer 1 t=7.12 min; Isomer 2 t=7.59 min. A solution ofN-Boc derivative (178 mg, 0.48 mmol) in 1N HCl/EtOAc (10 mL) was stirredovernight at room temperature. Solvent was removed under reducedpressure and residue washed with Et₂O to afford the title compound (80%)a white solid. MS m/z 268.4 (M⁺+1).

Method B

[1271] To a solution of the product of Preparation NA5 (0.75 g, 2.41mmol) in anhydrous DMF (10 mL), K₂CO₃ (1.66 g, 12.05 mmol) andbromoethane (0.54 mL, 7.23 mmol) were added. Reaction was stirred atroom temperature for 60 hours. Mixture was diluted with EtOAc and washedwith brine, dried (Na₂SO₄), filtered and evaporated. The residue waspurified by column chromatography (EtOAc, then EtOAcMeOH-Et₃N 90:5:5) toafford the N-Boc protected product as a yellow oil (MS m/z 368.4, M⁺+1).A solution of the N-Boc derivative (551 mg, 1.5 mmol) in 1N HCl/EtOAc(25 mL) was stirred for 2 h at room temperature. Solvent was removedunder reduced pressure and residue washed with Et₂O to afford the titlecompound (62%) a pale yellow solid. MS m/z 268.3 (M⁺+1). Enantiomer Awas obtained from Enantiomer I of Preparation NA5. Enantiomer B wasobtained from Enantiomer II of Preparation NA5.

Preparation NA7

[1272]

[1273] N-(2-Cyclohexy1-2-piperazin-1-yl-ethyl)-methanesulfonanidedihydrochloride salt

Method A

[1274] To a solution of the product of Preparation NA2 (2.82 g,. 9.08mmol) in dry 1,2-dichloroethane (50 mL), MeSO₂NH₂ (0.95 g, 9.99 mmol),sodium triacetoxyborohydride (3.85 g, 18.16 mmol) and Et₃N (2.5 mL,18.16 mmol) were added. Mixture was stirred overnight at roomtemperature and then ACOH (1.3 mL, 22.7 mmol), sodiumtriacetoxyborohydride (1.93 g, 9.08 mmol) were added. Reaction mixturewas stirred at room temperature for 24 hours and then diluted withCH₂Cl₂ (50 mL). Mixture was washed with brine, dried (Na₂SO₄), filteredand evaporated. The residue was purified by column chromatography(hexane-EtOAc 3:1) to afford the N-Boc protected product as a paleyellow oil (MS m/z 390.6 (M⁺1)). Enantiomers of this N-Boc protectedproduct could be separated by chiral HPLC (CHIRALPAK AD (4.6×250 mm),hexane-TFA 0.05%/isopropanol (9:1) isocratic mode, 1 mL/min). Isomer 1t=10.9 min; Isomer 2 t=11.9 min. A solution of N-Boc derivative (195 mg,0.50 mmol) in 1N HCl/EtOAc (20 mL) was stirred for 2 h at roomtemperature. Solvent was removed under reduced pressure and residuewashed with Et₂O to afford the title compound (14%) as a pale yellowsolid. MS m/z 290.6 (M⁺1).

Method B

[1275] To a solution of the product of Preparation NA5 (1.08 g, 3.47mmol) in anhydrous CH₂Cl₂ (25 mL) under nitrogen at 0° C., Et₃N (0.97mL, 6.95 mmol) and MeSO₂Cl (0.27 mL, 3.47 mmol) were added. After 30minutes at room temperature, solvent was removed under reduced pressureand the residue was purified by column chromatography (hexane-EtOAc 1:1)to afford the N-Boc protected product as an oil. A solution of the N-Bocderivative (0.18 g, 0.46 mmol) in 1N HCl/EtOAc (20 mL) was stirred atroom temperature overnight. A white solid appeared. Solvent was removedunder reduced pressure and the solid washed twice with Et₂O to affordthe title compound (70%) as a white solid. MS m/z 290.6 (M⁺+1).Enantiomer A was obtained from Enantiomer I of Preparation NA5.Enantiomer B was obtained from Enantiomer II of Preparation NA5.

Preparation NA8

[1276]

[1277]N-(2-Cyclohexyl-2-piperazin-1-yl-ethyl)-N-ethyl-methanesulfonamidedihydrochloride salt

Method A

[1278] Step I: Preparation of4-(1-cyclohexyl-2-ethylamino-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

[1279] To a solution of the product of Preparation NA2 (1.48 g, 4.8mmol) in 1,2-dichloroethane (10 mL) at room temperature was added EtNH₂(70% in H₂O, 0.3 mL, 5.7 mmol). After 10 min, sodiumtriacetoxyborohydride (1.5 g, 7.2 mmol) was added. Reaction was stirredfor 30 min and then quenched with a saturated aqueous solution of NaHCO₃(2 mL) and diluted with EtOAc (20 mL). Mixture was filtered throughCelite and solvent was removed under reduced pressure. Residue waspurified by column chromatography (EtOAc, then EtOAc-MeOH-Et₃N 90:5:5)to give the N-Boc protected product (99%) as an oil. MS m/z 340.3 (M⁺+1)

[1280] Step II: Preparation ofN-(2-Cyclohexyl-2-piperazin-1-yl-ethyl)-N-ethyl-methanesulfonamidedihydrochloride salt

[1281] To a solution of the product of Step I (1.5 g, 4.5 mmol) inanhydrous CH₂Cl₂ (15 mL) under nitrogen at 0° C., Et₃N (1.28 mL, 9.16tnfnol) and MeSO₂Cl (0.7 mL, 9.16 mmol) were added. After 10 minutessolvent was removed under reduced pressure and the crude obtained wassuspended in a mixture hexane/EtOAc (2:1). The insoluble solids werefiltered off and the filtrate concentrated. Residue was purified bycolumn chromatography (hexane-EtOAc 2:1) to afford the N-Boc protectedproduct as an oil. MS m/z 418.3 (M⁺+1). Enantiomers of this N-Bocprotected product could be separated by chiral HPLC (CHIRALPAK AD 20 μm,Hexane/isopropanol (7:3), isocratic mode, 1 mL/min). Isomer 1 t=4.18min; Isomer 2 t=4.67 min. A solution of N-Boc derivative (1.5 g, 4.5mmol) in 1N HCl/EtOAc (50 mL) was stirred at room temperature overnight.A white solid appeared. Solvent was removed under reduced pressure andthe solid washed twice with EtOAc to afford the title compound (75%) awhite solid. MS m/z 318.3 (M⁺+1).

Method B

[1282] Enantiomer A was obtained from Enantiomer I of Preparation NA5.Enantiomer B was obtained from Enantiomer II of Preparation NA5.

[1283] Step I: Preparation of4-(2-Acetylamino-1-cyclohexyl-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

[1284] To a solution of the product of Preparation NA5 (2.1 g, 6.78mmol) in anhydrous CH₂Cl₂, pyridine (1.1 mL, 13.5 mmol) and Ac₂O (0.83mL, 8.1 mmol) were added. The mixture was stirred for 2 h at roomtemperature. Then, the mixture was diluted with CH₂Cl₂ (20 mL) andwashed with water, 1N HCl, and brine. The organic phase was dried(Na₂SO₄), filtered and evaporated to afford the title compound (63%) asan oil. MS m/z 354.2 (M⁺+1)

[1285] Step II: Preparation of4-(1-cyclohexyl-2-ethylamino-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

[1286] To a solution of the product of Step I (397 mg, 1.12 mmol) inanhydrous THF (5.1 miL), a 1M solution of BH₃-THF complex in THF (3.4mL, 3.4 mmol) was added. The mixture was heated at 60° C. for 1 h andthen cooled to room temperature. Then, MeOH (1.5 mL) and DIPEA (0.760mL) were added. To this mixture, a solution of iodine (562 mg, 2.24mmol) in anhydrous THF (2.6 mL) was cautiously added and stirred at roomtemperature for 30 min. The reaction was diluted with EtOAc (75 mL) andthe organic phase was washed with 1N Na₂S₂O₃ and H₂O, dried (MgSO₄),filtered and concentrated under reduced pressure. The residue waspurified through a SCX column to afford the title compound (86%) as anoil. MS m/z 340.3 (M⁺+1).

[1287] Step III: Preparation ofN-(2-Cyclohexyl-2-piperazin-1-yl-ethyl)-N-ethyl-methanesulfonamidedihydrochloride salt

[1288] Following the general procedure described in Step II of Method Ain Preparation NA8, and using the product of Step II as startingmaterial, the title compound was prepared. MS m/z 318.3 (M⁺+1).Enantiomer A was obtained from Enantiomer I of Preparation NA5.Enantiomer B was obtained from Enantiomer II of Preparation NA5.

Preparation NA9

[1289]

[1290] 1-(1-Cyclohexyl-2-pyrrolidin-1-yl-ethyl)-piperazinetrihydrochloride salt

[1291] Following the general procedure described in Method A ofPreparation NA6, using pyrrolidine and the product of Preparation NA19as starting materials, the title compound was prepared (19%). MS m/z266.0 (M⁺+1)

Preparation NA10

[1292]

[1293] 2-(2-Cyclohexyl-2-piperazin-1-yl-ethyl)-isoindole-1,3-dionedihydrochloride salt

[1294] A solution of the product of Preparation NA4 (0.5 g, 1.13 mmol)in 1N HCl/EtOAc (25 mL) was stirred at room temperature for 5 h. Solventwas removed under reduced pressure and solid washed twice with Et₂O toafford the title compound (96%) a white solid. MS m/z 342.3 (M⁺+1)

Preparation NA11

[1295]

[1296]N-Benzyl-N-(2-cyclohexyl-2-piperazin-1-yl-ethyl)-methanesulfonamidedihydrochloride salt

[1297] Following the general procedure described in Method A ofPreparation NA8, using benzylamine and the product of Preparation NA2 inStep I as starting materials, the title compound was prepared (12%). MSm/z 380.6 (M⁺+1)

Preparation NA12

[1298]

[1299] N-(2-Cyclohexyl-2-piperazin-1-yl-ethyl)-acetarnidedihydrochloride salt

[1300] To a solution of the product of Preparation NA5 (2.1 g, 6.78mmol) in anhydrous CH₂Cl₂ (20 mL), pyridine (1.1 mL, 13.5 mmol) and Ac₂O(0.83 mL, 8.1 mmol) were added. The mixture was stirred for 2 h at roomtemperature. Then, the mixture was diluted with CH₂Cl₂ (20 mL) andwashed with water, 1N HCl, and brine. The organic phase was dried(Na₂SO₄), filtered and evaporated to afford the N-Boc protected amide asan oil. MS m/z 354.2 (M⁺+1). A solution of the N-Boc derivative (0.5 g,1.4 mmol) in 1N HCl/EtOAc (25 mL) was stirred at room temperature for 5h. Solvent was removed under reduced pressure and solid washed twicewith Et₂O to afford the title compound (59%) as a white solid. MS m/z254.3 (M⁺+1).

Preparation NA13

[1301]

[1302] N-(2-Cyclohexyl-2-piperazin-lyl-ethyl)-N-ethyl-acetamidedihydrochloride salt

[1303] To a solution of the product of Step II of Method B inPreparation NA8 (325 mg, 0.96 mmol) in anhydrous pyridine (1.8 mL) atroom temperature, Ac₂O (1.8 mL) was added. The mixture was stirred for 1h at 65° C. and then cooled to room temperature. The mixture was dilutedwith EtOAc (40 mL) and washed with a saturated aqueous solution ofNaHCO₃, H₂O, and brine. The organic phase was dried (MgSO₄), filteredand concentrated under reduced pressure The residue was purified bycolumn chromatography (hexane-EtOAc 1:1) to afford the N-Boc protectedamide as an oil. A solution of the N-Boc derivative (109 mg, 0.29 mmol)in 1N HCl/EtOAc (20 mL) was stirred at room temperature overnight.Solvent was removed under reduced pressure and solid washed twice withEt₂O to afford the title compound (30%) as a white solid. MS m/z 282.3(M⁺+1).

[1304] Enantiomer A was obtained from Enantiomer A of Step II of MethodB in Preparation NA8. Enantiomer B was obtained from enantiomer B ofStep II of Method B in Preparation NA8.

Preparation NA14

[1305]

[1306] 1-(2-Cyclohexyl-2-piperazin-1-yl-ethyl)-pyrrolidin-2-onedihydrochloride salt Enantiomer A was obtained from Enantiomer I ofPreparation NA5. Enantiomer B was obtained from Enantiomer II ofPreparation NA5.

[1307] Step I: Preparation of4-[2-(4-Chloro-butyrylamino)-1-cyclohexyl-ethyl]-piperazine-1-carboxylicacid tert-butyl ester

[1308] To a solution of the product of Preparation NA5 (1.0 g, 3.21mmol) in CH₂Cl₂ (18 EL) and DMF (4.4 mL), DIPEA (2.8 mL, 16.05 mmol),4-chlorobutyric acid (0.381 mL, 385 mmol), HOAT (546 mg, 4.01 mmol), andHATU (1.52 mg, 4.01 mmol) were added at room temperature. The mixturewas stirred overnight at room temperature. Then, H₂O was added and thelayers were separated. The aqueous phase was extracted with CH₂Cl₂ andthe combined organic layers were dried (MgSO₄), filtered andconcentrated under reduced pressure. The crude was purified by columnchromatography (hexane-EtOAc 7:3) to afford the title compound (69%) asan oil. MS m/z 416.2 (M⁺+1).

[1309] Step II: Preparation of1-(2-Cyclohexyl-2-piperazin-1-yl-ethyl)-pyrrolidin-2-one dihydrochloridesalt

[1310] To a solution of the product of Step I (538 mg, 1.29 mmol), inanhydrous THF (7.7 mL) at 0° C., potassium tert-butoxide (145 mg, 1.29mmol) was added. After stirring for 1.5 h, additional potassiumtert-butoxide (145 mg, 1.29 mmol) was added and mixture stirred for 30min. Reaction was quenched with H₂O and aqueous layer extracted withEtOAc. The combined organic phase was dried (MgSO₄), filtered andevaporated. The residue was purified by column chromatography(hexane/EtOAc 1:1) to afford the N-Boc protected product as an oil. Asolution of the N-Boc derivative (266 mg, 0.70 mmol) in 1N HCl/EtOAc (25mL) was stirred at room temperature overnight. Solvent was removed underreduced pressure and solid washed twice with Et₂O to afford the titlecompound (54%) as a white solid. MS m/z 280.2 (M⁺+1).

Preparation NA15

[1311]

[1312] 1-(2-Cycloheyl-2-piperazin-1-yl-ethyl)-pyrrolidin-2,5-dionedihydrochloride salt

Method A

[1313] To a solution of the product of Preparation NA1 (300 mg, 0.96mmol) in anhydrous THF (4.8 mL) at 0° C., succinimide (105 mg, 1.06mmol) and triphenylphosphine (278 mg, 1.06 mmol) were added. Then, DEAD(0.167 mL, 1.06-mmol) was added dropwise at 0° C. and the reaction wasstirred at 0° C. for 1 h and at room temperature overnight. The mixturewas concentrated under reduced pressure and the residue purified bycolumn chromatography (hexane/EtOAc 1:1) to afford the N-Boc protectedproduct as an oil. A solution of the N-Boc derivative (291 mg, 0.74mmol) in 1N HCl/EtoAc (20 mL) was stirred at room temperature overnight.Solvent was removed under reduced pressure and solid washed twice withEt₂O to afford the title compound (77%) as a white solid. MS m/z 293.9(M⁺+1)

Method B

[1314] Enantiomer A was obtained from Enantiomer I of Preparation NA5.Enantiomer B was obtained from Enantiomer II of Preparation NA5.

[1315] To a solution of the product of Preparation NA5 (0.641 g, 2.05mmol) in CHCl₃ (2 mL) and succinic anhydride (205 mg, 2.05 mmol) wereadded at room temperature. The mixture was stirred under reflux for 1hour and then it was heated at 120° C. for another 2 hours. The crudewas purified by column chromatography (hexane/EtOAc 1:1) to afford 645mg (83%) of the N-Boc protected product as white solid. A solution ofthe N-Boc derivative (645 mg, 1.64 mmol) in 1N HCl/EtOAc (25 mL) wasstirred at room temperature overnight. Solvent was removed under reducedto afford the title compound as a white solid. MS m/z 293.9 (M⁺+1)

Preparation NA16

[1316]

[1317] 2-Cyclohexyl-N,N-diethyl-2-piperazin-1-yl-acetamidedihydrochloride salt

[1318] To a solution of the product of Preparation NA3 (300 mg, 0.92mmol) in CH₂Cl₂ (4.8 mL) and DMF (1 mL) at room temperature, DIPEA (0.8mL, 4.6 mmol), diethylamine (0.114 mL, 1.10 mmol) and HOBT (155 mg, 1.15mmol) were added and the mixture stirred for 5 min. Then, EDCI (220 mg,1.15 mmol) was added and the reaction stirred overnight at roomtemperature. Then, H₂O (10 mL) was added and mixture diluted with CH₂Cl₂(10 mL). The layers were separated and the aqueous phase was extractedwith CH₂Cl₂. The combined organic layers were dried (MgSO₄), filteredand evaporated under reduced pressure. The residue was purified bycolumn chromatography (hexane/EtOAc 7:3) to afford the N-Boc protectedamide as an oil. Enantiomers of this N-Boc protected product could beseparated by chiral HPLC (CHIRALPAK AD (4.6×250mm), hexane-TFA0.05%/isopropanol (20:1) isocratic mode, 1 mL/min). Isomer 1 t=7.59 min;Isomer 2 t=8.8l1min. A solution of the N-Boc derivative (203 mg, 0.53mmol) in 1N HCl/EtOAc (20 mL) was stirred at room temperature overnight.Solvent was removed under reduced pressure and solid washed twice withEt₂O to afford the title compound (58%) as a white solid. MS m/z 281.9(M⁺+1).

Preparation NA17

[1319]

[1320] 2-Cyclohexyl-2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanonedihydrochloride salt

[1321] Following the general procedure described in Preparation NA16,and using pyrrolidine and the product of Preparation NA3 as startingmaterials, the title compound was prepared (40%). MS m/z 279.8 (M⁺+1).

Preparation NA18

[1322]

[1323] 4-(1-Cyclohexylmethyl-2-hydroxy-ethyl)-piperazine-1-carboxylicacid tert-butyl ester

[1324] Following the general procedure described in Preparation NA1, andusing 3-cyclohenxylpropionic acid as starting material, the titlecompound was prepared (49%). MS m/z 327.2 (M⁺+1)

Preparation NA19

[1325]

[1326] 4-(1-Cyclohexylmethyl-2-oxo-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

[1327] Following the general procedure described in Preparation NA2, andusing the product of Preparation NA18 as starting material, the titlecompound was prepared (95%). MS m/z 325.4 (M⁺+1)

Preparation NA20

[1328]

[1329] (2-Cyclohexylmethyl-2-piperazin-1-yl-ethyl)-diethyl-aminetrihydrochloride salt

[1330] Following the general procedure described in Method A ofPreparation NA6, using diethylamine and the product of Preparation NA19as starting materials, the title compound was prepared (68%). MS m/z282.3 (M⁺+1).

Preparation NA21

[1331]

[1332] 1-(1-Cyclohexylmethyl-2-pyrrolidin-1-yl-ethyl)-piperazinetrihydrochloride salt

[1333] Following the general procedure described in Method A ofPreparation NA6, using pyrrolidine and the product of Preparation NA19as starting materials, the title compound was prepared (76%). MS m/z280.4 (M⁺+1).

Preparation NA22

[1334]

[1335] 1-(1-Cyclohexylmethyl-2-piperidin-1-yl-ethyl)-piperazinetrihydrochloride salt

[1336] Following the general procedure described in Method A ofPreparation NA6, using piperidine and the product of Preparation NA19 asstarting materials, the title compound was prepared (70%). MS m/z 294.2(M⁺+1).

Preparation NA23

[1337]

[1338] 4-(3-Cyclohexyl-2-piperazin-1-yl-propyl)-morpholinetrihydrochloride salt

[1339] Following the general procedure described in Method A ofPreparation NA6, using morpholine and the product of Preparation NA19 asstarting materials, the title compound was prepared (65%). MS m/z 296.6(M⁺+1).

Preparation NA24

[1340]

[1341] N-(3 -Cyclohexyl-2-piperazin-1-yl-propyl)-methanesulfonamidedihydrochloride salt

[1342] Step I: Preparation of4-[(1-Cyclohexylmethyl-2-hydroxyimino-ethyl)-piperazine-1-carboxylicacid tert-butyl ester

[1343] Following the procedure described in Step I of Method B inPreparation NA4, using the product of Preparation NA19 as startingmaterials, the title compound was prepared (46%). MS m/z 340.3 (M⁺+1).

[1344] Step II: Preparation ofN-(3-Cyclohexyl-2-piperazin-1-yl-propyl)-methanesulfonamidedihydrochloride salt

[1345] To a solution of NiCl₂.6H₂O (533 mg, 2.24 mmol) in MeOH (25 mL),NaBH₄ (85 mg, 2.24 mmol) was added. To the resulting black solution, asolution of the product of Step I (760 mg, 2.24 mmol) in MeOH (10 mL)was added, followed by NaBH₄ (465 mg, 12.3 mmol) portionwise. Themixture was stirred for 5 min and filtered through celite. The solutionwas diluted with EtOAc and washed with a 5% aqueous solution of NH₄OH,dried, filtered and evaporated to afford the primary amine. To asolution of this amine (676 mg, 2.08 mmol) in anhydrous CH₂Cl₂ (20 mL)under nitrogen at 0° C., Et₃N (0.43 mL, 3.12 mmol) and MeSO₂Cl (0.24 mL,3.12 mmol) were added. After 30 minutes at room temperature, solvent wasremoved under reduced pressure and the residue was purified by columnchromatography (hexane-EtOAc 1:1) to afford the N-Boc protected productas an oil. A solution of the N-Boc derivative (440 mg, 1.09 mmol) in 1NHCl/EtOAc (25 mL) was stirred at room temperature for 2 h. A white solidappeared. Solvent was removed under reduced pressure and the solidwashed twice with Et₂O to afford the title compound as a solid (35%). MSm/z 304.6 (M⁺+1).

Preparation NA25

[1346]

[1347]N-(3-Cyclohexyl-2-piperazin-1-yl-propyl)-N-ethyl-methanesulfonamidedihydrochloride salt

[1348] Following the general procedure described in Method A ofPreparation NA8, using ethylamine and the product of Preparation NA19 asstarting materials, the title compound was prepared (59%). MS m/z 332.3(M⁺+1)

Preparation NA26

[1349]

[1350] 4-(1-Cyclopentyl-2-hydroxy-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

[1351] Following the general procedure described in Preparation NA1, andusing cyclopentylacetic acid as starting material, the title compoundwas prepared (16%). MS m/z 299.2 (M⁺+1)

Preparation NA27

[1352]

[1353] 4-(1-Cyclopentyl-2-oxo-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

[1354] Following the general procedure described in Preparation NA2, andusing the product of Preparation NA26 as starting material, the titlecompound was prepared (99%). MS m/z 297.3 (M⁺+1)

Preparation NA28

[1355]

[1356] (2-Cyclopentyl-2-piperazin-1-yl-ethyl)-diethyl-arninetrihydrochloride salt

[1357] Following the general procedure described in Preparation NA6, andusing the product of Preparation NA27 as starting material, thisintermediate was prepared (86%). MS m/z 254.3 (M⁺+1)

Preparation NA29

[1358]

[1359]N-(2-Cyclopentyl-2-piperazin-1-yl-ethyl)-N-ethyl-methanesulfonamidedihydrochloride salt

[1360] Following the general procedure described in Preparation NA8, andusing the product of Preparation NA27 as starting material, the titlecompound was prepared (24%). MS m/z 304.2 (M⁺+1).

Preparation NA30

[1361]

[1362] 4-(1-Cycloheptyl-2-hydroxy-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

[1363] Following the general procedure described in Preparation NA1, andusing cycloheptylacetic acid as starting material, the title compoundwas prepared (40%). MS m/z 327.4 (M⁺+1).

Preparation NA31

[1364]

[1365] 4-(1-Cycloheptyl-2-oxo-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

[1366] Following the general procedure described in Preparation NA2, andusing the product of Preparation NA30 as starting material, the titlecompound was prepared (91%). MS m/z 325.4 (M⁺+1).

Preparation NA32

[1367]

[1368] (2-Cycloheptyl-2-piperazin-1-yl-ethyl)-diethyl-aminetrihydrochloride salt

[1369] Following the general procedure described in Preparation NA6, andusing the product of Preparation NA31 as starting material, the titlecompound was prepared (44%). MS m/z 282.6 (M⁺+1).

Preparation NA33

[1370]

[1371] (2S)-Diethyl-(2-phenyl-2-piperazin-1-yl-ethyl)-aminetrihydrochloride salt

[1372] Step I: Preparation of (2R)-2-Diethylamino-2-phenyl-ethanol

[1373] To a solution of (R)-phenylglycinol (0.5 g, 3.6 mmol) in THF (15mL) under nitrogen.atmosphere, Na₂CO₃ (1.14 g, 10.8 mmol),tetrabutylammonium iodide (0.66 g, 1.8 mmol) and ethyl iodide (0.6 mmol,7.3 mmol) were added. The reaction was stirred under reflux for 24hours. The resulting mixture was cooled to room temperature and thesolids filtered off. The filtrated was concentrated under reducedpressure and the residue was dissolved in EtOAc, washed with H₂O, dried(Na₂SO₄), filtered and evaporated under reduced pressure. The crudeproduct was purified by column chromatography (EtOAc-MeOH-Et₃N 90:5:5)to afford the title compound (96%). MS m/z 194.2 (M⁺+1)

[1374] Step II: Preparation of(2S)-Diethyl-(2-phenyl-2-piperazin-1-yl-ethyl)-amine trihydrochloridesalt

[1375] To a solution of the product of Step I (0.68 g, 3.5 mmol) inanhydrous Et₂O (10 mL) under nitrogen atmosphere, Et₃N (1.4 mL, 10.5mmol) was added. The mixture was cooled to 0° C. and methanesulfonylchloride (0.4 mL, 4.9 mmol) was added dropwise. The mixture was allowedto react at room temperature and stirred for 30 min. Then,N-Bocpiperazine (1.3 g, 7.2 mmol) was added and the reaction was stirredat room temperature overnight. The mixture was diluted with EtOAc (10mL) and washed with H₂O (5 mL). The phases were separated and theorganic layer was dried (Na₂SO₄), filtered and evaporated under reducedpressure. The residue was purified by medium pressure chromatography(EtOAc-MeOH-Et₃N 90:5:5) to afford the N-Boc protected product in >98%ee. (determined by chiral HPLC Chiralpak AD, Hexane-TFA 0.05%, 1 mL/min,t=9.748). A solution of the N-Boc derivative (0.68 g, 1.88 mmol) in 1NHCl/EtOAc (25 mL) was stirred overnight at room temperature. Solvent wasremoved under reduced pressure and residue washed with Et₂O to affordthe title compound (52%) a white solid. MS m/z 262.2 (M⁺+1).

Preparation NA34

[1376]

[1377] (2R)-Diethyl-(2-phenyl-2-piperazin-1-yl-ethyl)-aminetrihydrochloride salt

[1378] Following the general procedure described in Preparation NA37,and using (S)-phenylglycinol as starting material, the title compoundwas prepared. MS m/z 262.2 (M⁺+1).

Preparation NA35

[1379]

[1380] 4-(1-Methoxycarbonyl-2-phenyl-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

[1381] Step I: Preparation of 3-Bromo-4-phenyl-butyric acid methyl ester

[1382] Following the general procedure described in Method A of Step Iin Preparation NA1, using 3-phenylpropionic acid as starting material,the title compound was prepared (37%) . MS m/z 243.0 (M⁺+1).

[1383] Step II: Preparation of4-(1-Methoxycarbonyl-2-phenyl-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

[1384] Following the general procedure described in Step II ofPreparation NA1, using the product of Step I as starting material, thetitle compound was prepared (24%). MS m/z 349.2 (M⁺+1).

Preparation NA36

[1385]

[1386] 4-(1-Formyl-2-phenyl-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

[1387] To a solution of the product of Preparation NA39 (inffra) (2.41g, 6.92 mmol) in CH₂Cl₂ (40 mL) at −78° C. under nitrogen atmosphere, a1M solution of DIBAL-H in toluene (17.3 mL, 17.3 mmol) was added.Reaction was stirred for 1 hour (h) at −78° C. and quenched with asaturated aqueous solution of sodium tartrate. Mixture was stirred for 1hour and layers separated. Aqueous layer was extracted with CH₂Cl₂,dried (Na₂SO₄), filtered and evaporated. The residue was purified bycolumn chromatography (hexane-EtOAc 5:1) to afford the title compound asa pale yellow oil (56%). MS m/z 319.4 (M⁺+1).

Preparation NA37

[1388]

[1389] Diethyl-(3-phenyl-2-piperazin-1-yl-propyl)-amine trihydrochloridesalt

[1390] Following the general procedure described in Method A ofPreparation NA6, using diethylamine and the product of Preparation NA40as starting materials, the title compound was prepared (41%). MS m/z276.5 (M⁺+1).

Preparation NA38

[1391]

[1392] Diethyl-(2-piperazin-1-yl-2-pyridin-2-yl-ethyl)-aminetretrahydrochloride salt

[1393] Step I: Preparation of4-7(Ethoxycarbonyl-pyridin-2-yl-methyl)-piperazine-1-carboxylic acidtert-butyl ester

[1394] To a solution of ethyl 2-pyridylacetate (3.0 g, 18.16 mmol) inCCl₄ (26 mL), NBS (3.56 g, 20.0 nmuol), AIBN (149 mg, 0.91 mmol) wereadded at room temperature. The reaction mixture was allowed to stirunder reflux for 5 hours. The resulting brown suspension was cooled toroom temperature and water and CH₂Cl₂ were added. The layers wereseparated and the organic layer was washed with water. Then it was dried(MgSO₄), filtered and concentrated under reduced pressure to afford thebromide derivative as brown oil. To a solution of this product (3.69 g,15.12 mmol) in anhydrous CH₃CN (36 mL), K₂CO₃ (4.19 g, 30.24 mmol),N-Boc-piperazine (3.09 g, 16.63 mmol), and a catalytic amount of nBu₄NI(559 mg, 1.51 mmol) were added. The mixture was heated under refluxovernight and then cooled to room temperature. Reaction was diluted withEtOAc, washed with H₂O and brine, dried (MgSO₄) and evaporated underreduced pressure. The residue was purified by column chromatography(hexane-EtOAc 1:1) to afford the title compound (17%) as a yellow oil.MS m/z 350.4 (M⁺+1).

[1395] Step II: Preparation of4-(2-Oxo-1-pyridin-2-yl-ethyl)-piperazine-1-carboxylic acid tert-butylester

[1396] To a solution of product from Step I (803 mg, 2.3 rnmol) in dryCH₂Cl₂ (5.4 mL) at −78° C., under N₂ atmosphere, a 1.0 M solution ofDIBAL-H in toluene (5.8 mL, 5.8 mmol) was added dropwise. The reactionmixture was allowed to stir at this temperature for about 30 minutes.Then it was quenched with MeOH (imL) slowly. Then EtOAc (50 mL) and asaturated solution of sodium tartrate (50 mL) were added. After stirringat RT for 1 hour the layers were separated and the aqueous phase wasextracted with EtOAc. The combined organic phase was dried over MgSO4,filtered and concentrated in vacuo to afford the title compound as anoil. MS m/z 306.4 (M⁺+1).

[1397] Step III: Preparation ofDiethyl-(2-piperazin-1-yl-2-pyridin-2-yl-ethyl)-aminetretrahydrochloride salt

[1398] To a solution of product from Step II (624 mg, 2.05 mmol) in dry1,2-dichloroethane (7.2 mL), diethylamine (0.254 mL, 2.46 mmol) wasadded at room temperature. The mixture was stirred for 15 min and thensodium triacetoxyborohydride (652 mg, 3.08 mmol) was added. Reactionmixture was stirred at room temperature overnight and then quenched witha saturated aqueous solution of NaHCO₃. Layers were separated andaqueous phase was extracted with EtOAc (3×). The combined organic layerswere dried (MgSO₄), filtered and concentrated under reduced pressure.Residue was purified by column chromatography (EtOAc, thenEtOAc-MeOH-Et₃N 90:5:5) to give the N-Boc protected product as an oil. Asolution of N-Boc derivative (208 mg, 0.57 mmol) in saturatedHCl(g)/MeOH (10 mL) was stirred overnight at room temperature. Solventwas removed under reduced pressure to afford the title compound (26%) asa white solid. MS m/z 263.4 (M⁺+1).

Preparation NA39

[1399]

[1400] 1-(1-Cyclohexyl-3-methyl-but-2-enyl)-piperazine dihydrochloridesalt

[1401] Step I: Preparation of4-(1-Cyclohexyl-3-methyl-but-2-enyl)-piperazine-1-carboxylic acidtert-butyl ester

[1402] To a solution of isopropyltriphenylphosphonium iodide (709 mg,1.79 mmol) cooled at −78° C. was added n-butyllithium (0.98 mL, 1.57mtnol, 1.6 M in hexanes) and stirred for 1 hour while warming to 0° C.The mixture was added to a solution of product of Preparation NA2 (443mg, 1.43 mmol) at −78° C. and stirred at 23° C. for 2 hours. Thereaction was diluted with EtOAC and washed with brine, the combinedorganic phase was dried (Na₂SO₄), dried, and evaporated. The residue waspurified by flash chromatography (hexane-EtOAc 15:1) to afford the titlecompound (385 mg). MS m/z 337.3 (M⁺+1).

[1403] Step II: Preparation of1-(1-Cyclohewyl-3-methyl-but-2-enyl)-piperazine dihydrochloride salt

[1404] A solution of the N-Boc derivative (250 mg, 0.74 mmol) in 1NHCl/EtOAc (25 mL) was stirred at room temperature overnight. Solvent wasremoved under reduced pressure and solid washed twice with Et₂O toafford the title compound as a white solid. MS m/z 237.3 (M⁺+1).

Preparation NA40

[1405]

[1406] 1-(1-Cyclohexyl-3-methyl-butyl)-piperazine dihydrochloride salt

[1407] Step I: Preparation of4-(Cyano-cyclohexyl-methyl)-piperazine-1-carboxylic tert-butyl ester

[1408] To a solution of KCN (1.61 g, 24.8 mmol) in H₂O (15 mL)N-Boc-piperazine (4.6 g, 24.6 mmol) was added and the mixture cooled to0° C. Then 1M aqueous HCl (23.9 mL, 23.9 mmol) wan added followed bycyclohexanecarboxaldehyde (2.0 mL, 16.5 mmol) and the mixture stirredfor 20 h. It was poured over Et₂O and the aqueous phase extracted withEt₂O, dried (MgSO₄), and evaporated. The crude was purified by flashchromatography (hexane-EtOAc 4:1→3:1) to afford 4.2 g of the titlecompound.

[1409] Step II: Preparation of4-(1-Cyclohexyl-3-methyl-butyl)-piperazine-1-carboxylic acid tert-butylester

[1410] A solution of product from Step I (750 mg, 2.44 mmol) in THF (15mL) and isobutylmagnesium bromide (6.1 mL, 12.2 mmol, 2 M in THF) washeated at 70° C. for 24 h. The reaction was quenched with EtOAc andwashed with brine, dried (Na₂SO₄), and evaporated. Final purification byflash chromatography (hexane-EtOAc 25:1) afforded,406 mg of the titlecompound. MS m/z 339.3 (M⁺+1).

[1411] Step III: Preparation of1-(1-Cyclohexyl-3-methyl-butyl)-piperazine dihydrochloride salt

[1412] A solution of the product from Step II (406 mg, 1.21 mmol) in 1NHCl/EtOAc (25 mL) was stirred at room temperature overnight. Solvent wasremoved under reduced pressure and solid washed twice with Et₂O toafford the title compound as a white solid. MS m/z 239.3 (M⁺+1).

Preparation NA41

[1413]

[1414] 1-(2-Cyclohexyl-1-cyclohexylmethyl-ethyl)-piperazinedihydrochloride salt

[1415] Step I: Preparation of4-(1-Cyano-2-cyclohexyl-ethyl)-piperazine-1-carboxylic acid tert-butylester

[1416] A solution of cyclohexaneacetaldehyde (8.45 g, 66.96 mmol) andTMSCN (17.9 mL, 133.92 mmol) in MeOH was stirred for 2 h at 23° C. andN-BOC-piperazine (13.72 g, 73.66 mmol) was added. After 24 the solventwas evaporated to give the title compound.

[1417] Step II: Preparation of4-(2-Cyclohexyl-1-cyclohexylmethyl-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

[1418] A solution of4-(1-cyano-2-cyclohexyl-ethyl)-piperazine-1-carboxylic acid tert-butylester (1.81, 5.65 mmol) in THF (20 mL) and cyclohexylmethylmagnesiumbromide (1.51 g, 22.60 mmol, 0.4 M in Et₂O) was stirred at 23° C. for 24h. The reaction was quenched with EtOAc and washed with brine, dried(Na₂SO₄), and evaporated. Final purification by flash chromatography(hexane-EtOAc 15:1) afforded 1020 mg of the title compound. MS m/z 393.3(M⁺+1).

[1419] Step III: Preparation of1-(2-Cyclohexyl-1-cyclohexylmethyl-ethyl)-piperazine dihydrochloridesalt

[1420] A solution of the N-Boc derivative (1020 mg, 2.60 mmol) in 1NHCl/EtOAc (25 mL) was stirred at room temperature overnight. Solvent wasremoved under reduced pressure and solid washed twice with Et₂O toafford the title compound as a white solid. MS m/z 293.3 (M⁺+1).

Preparation NA42

[1421]

[1422]N-(2-Cyclohexyl-2-piperazine-1-yl-ethyl)-N-isobutyl-methanesulfonamidedihydrochloride salt

[1423] Enantiomer A was obtained from Enantiomer I of Preparation NA5.Enantiomer B was obtained from Enantiomer II of Preparation NA5.

[1424] Step I: Preparation of4-(1-Cyclohexyl-2-isobutyrylamino-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

[1425] To a solution of the product of Preparation NA5 (1.0 g, 3.21nunol) in CH₂Cl₂ (10 mL) was added isobutyryl chloride (0.4 ml, 3.85mmol) and pyridine (0.39 mL, 4.82 mmol) at 0° C. and stirring for 1 hourwhile warming to 23° C. The mixture was diluted with CH₂Cl₂ and washedwith brine, dried (Na₂SO₄), and evaporated to give the title product asan oil. MS m/z 382.3 (M⁺+1).

[1426] Step II: Preparation of4-(1-Cyclohexyl-2-isobutylamino-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

[1427] A solution of the product from Step I (1.23 g, 3.21 mmol) andborane-tetrahydrofurane complex (9.6 mL, 9.63 mmol, 1 M in THF) in THF(20 mL) was heated at 60° C. for 1 hour. The mixture was allowed to coolto ambient temperature followed by addition of MeOH (5 mL) and DIPEA(7.5 mL). Next, iodine (1.62 g, 6.42 mmol) in THF (10 mL) was added andthe mixture stirred for 30 min. The mixture was diluted with EtOAc andsuccessively washed with 10% aqueous Na2S₂O₅ and brine, dried (Na₂SO₄),and evaporated. The residue was purified by flash chromatography(hexane:EtOAc 1:1→EtOAc→EtOAc:MeOH:NEt₃ 90:5:5) to afford the titlecompound (904 mg) as a yellow oil. MS m/z 368.3 (M⁺+1).

[1428] Step III: Preparation of4-[1-Cyclohexyl-2-(isobutyl-methanesulfonyl-amino)-ethyl]-piperazine-1-carboxylicacid tert-butyl ester

[1429] To a solution of the product from Step II (450 mg, 1.2 mmol) inCH₂Cl₂ (5 mL) was added TEA (0.35 mL, 2.44 mmol) and methanesulfonylchloride (0.14 mL, 1.83 mmol). After stirring was 30 min at 23° C. thereaction was diluted with CH₂Cl₂ and washed with brine, dried (Na₂SO₄),and evaporated to give the title product as an oil. MS m/z 446.3 (M⁺+1).

[1430] Step IV: Preparation ofN-(2-Cyclohexyl-2-piperazin-1-yl-ethyl)-N-isobutyl-methanesulfonamidedihydrochloride salt

[1431] A solution of the product from Step III (446 mg, 1.22 mmol) in 1NHCl/EtOAc (25 mL) was stirred at room temperature overnight. Solvent wasremoved under reduced pressure and solid washed twice with Et₂O toafford the title compound as a white solid. MS m/z 346.3 (M⁺+1).

Preparation NA43

[1432]

[1433] N-(2-Cyclohexyl-2-piperazine-1-yl-ethyl)-N-isobutyl-acetamidedihydrochloride salt

[1434] Enantiomer A was obtained from Enantiomer I of Preparation NA5.Enantiomer B was obtained from Enantiomer II of Preparation NA5.

[1435] Step I: Preparation of4-[2-(Acetyl-isobutyl-amino)-1-cyclohexyl-ethyl]-piperazine-1-carboxylicacid tert-butyl ester

[1436] To a solution of the product from Step II of Preparation NA42(450 mg, 1.22 mmol) in CH₂Cl₂ (5 mL) was added at 0° C. acetyl chloride(0.1 mL, 1.46 mmol) and pyridine (0.15 mL, 1.83 mmol). The cold bath wasremoved and the reaction was stirred for 1 hour at 23° C. The reactionmixture was diluted with CH₂Cl₂ and washed with brine, dried (Na₂SO₄),and evaporated to the title compound (500 mg). MS m/z 410.3 (M⁺+1).

[1437] Step II: Preparation ofN-(2-Cyclohexyl-2-piperazin-1-yl-ethyl)-N-isobutyl-acetamidedihydrochloride salt

[1438] A solution of the product from Step I (500 mg, 1.2.1 mmol) in 1NHCl/EtOAc (25 mL) was stirred at room temperature overnight. Solvent wasremoved under reduced pressure and solid washed twice with Et₂O toafford the title compound as a white solid. MS m/z 310.3 (M⁺+1).

Preparation NA44

[1439]

[1440] 1-Dicyclohexylmethyl-piperazine dihydrochloride salt

[1441] Step I: Preparation of4-Dicyclohexylmethyl-piperazine-1-carboxylic acid tert-butyl ester

[1442] A solution of product from Step I of Preparation NA40 (1.0 g,3.25 mmol) in THF (30 mL). and cyclohexylmagnesium chloride (8.1 mL,16.3 mmol, 2 M in THF) was heated at 70° C. for 72 h. After cooling to0° C., the reaction was quenched with a saturated aqueous solution ofNH₄Cl and extracted with EtOAc washed with brine, dried (Na₂SO₄), andevaporated. Final purification by flash chromatography (hexane-EtoAc15:1) afforded 205 mg of the title compound. MS m/z 364.9 (M⁺+1).

[1443] Step II: Preparation of 1-Dicyclohexylmethyl-piperazinedihydrochloride salt

[1444] A solution of the product from Step I (200 mg, 0.55 mmol) in 1NHCl/EtOAc (5.5 mL) was stirred at room temperature overnight. Solventwas removed under reduced pressure and solid washed twice with Et₂O toafford the title compound as a white solid. MS m/z 264.9 (M⁺+1).

EXAMPLE N1

[1445]

[1446] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amidetri(trifluoroacetate) salt.

[1447] A mixture of the racemic A domain compound of Preparation NA6(180 mg, 0.48 mmol, 1 eq.), the BC domain combination of Preparation BC1(273 mg, 0.58 mmol, 1.2 eq.), HOAT (82 mg, 0.60 mmol, 1.25 eq.), HATU(228 mg, 0.60 mmol, 1.25 eq.) and DIPEA (0.83 mL, 4.8 mmol, 10 eq.) wasstirred in CH₂Cl₂/DMF (4:1, v:v) (3.0 mL) at room temperature overnight.Extractive work up with EtOAc yielded the crude product that waspurified by column chromatography. A solution of the N-Boc protectedproduct in methylene chloride/TFA (1:1, v:v) was stirred at roomtemperature for 2 hours. Solvent was evaporated and residue washed withEt₂O to afford the title compound (51). MS m/z 608.6 (M⁺+1).

EXAMPLE N2

[1448]

[1449] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-(1-cyclopentyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amidetri(trifluoroacetate) salt

[1450] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA28 and the BCdomain combination of Preparation BC1. MS m/z 594.4 (M⁺+1).

EXAMPLE N3

[1451]

[1452] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-(1-cycloheptyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amidetrihydrochloride salt

[1453] A mixture of the racemic A domain compound of Preparation NA32(421 mg, 1.07 mmol, 1 eq.), the BC domain combination of Preparation BC1(567 mg, 1.23 mmol, 1.2 eq.), HOAT (183 mg, 1.34 mmol, 1.25 eq.), HATU(510 mg, 1.34 mmol, 1.25 eq.) and DIPEA (1.87 mL, 10.7 mmol, 10 eq.) wasstirred in CH₂Cl₂/DMF (4:1, v:v) (7.5 mL) at room temperature overnight.Extractive work up with EtOAc yielded the crude product that waspurified by column chromatography. A solution of the N-Boc protectedproduct in 1N HCl/EtOAc was stirred at room overnight. Solvent wasevaporated and residue washed with Et₂O to afford the title compound(79%). MS m/z 622.5 (M⁺+1).

EXAMPLE N4

[1454]

[1455] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl)-amidetri(trifluoroacetate) salt

[1456] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA20 and the BCdomain combination of Preparation BC1. MS m/z 622.4 (M⁺+1)

EXAMPLE N5

[1457]

[1458] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[1-cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amidedihydrochloride salt

[1459] According to the procedure described in Example N3, this compoundwas prepared from the racemic A domain of Preparation NA8 and the BCdomain combination of Preparation BC1. MS m/z 658.3 (M⁺+1)

EXAMPLE N6

[1460]

[1461] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[1-cyclopentyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amidedihydrochloride salt

[1462] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA29 and the BCdomain combination of Preparation BC1. MS m/z 644.4 (M⁺+1)

EXAMPLE N6

[1463]

[1464] 1,2,3,4-Tetrahydro-isoguinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[1-cyclohexylmethyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amidedihydrochloride salt

[1465] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA25 and the BCdomain combination of Preparation BCl. MS m/z 672.3 (M⁺+1)

EXAMPLE N7

[1466]

[1467] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-[1-cyclohexyl-2-methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amidedi(trifluoroacetate) salt

[1468] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA7 and the BCdomain combination of Preparation BC1. MS m/z 630.2 (M⁺+1)

EXAMPLE N8

[1469]

[1470] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amidetri(trifluoroacetate) salt

[1471] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA9 and the BCdomain combination of Preparation BC1. MS m/z 606.4 (M⁺+1)

EXAMPLE N9

[1472]

[1473] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid[2-{4-[2-(benzyl-methanesulfonyl-amino)-1-cyclohexyl-ethyl]-piperazin-1-yl}-1-(4-chloro-benzyl)-2-oxo-ethyl]-amidedihydrochloride salt

[1474] According to the procedure described in Example N3, this compoundwas prepared from the racemic A domain of Preparation NA11 and the BCdomain combination of Preparation BC1. MS m/z 720.4 (M⁺+1)

EXAMPLE N10

[1475]

[1476] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[1-cyclohexyl-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amidedi(trifluoroacetate) salt

[1477] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA10 and the BCdomain combination of Preparation BC1. MS m/z 682.4 (M⁺+1)

EXAMPLE N11

[1478]

[1479] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid[2-[4-[(2-acetylamino-1-cyclohexyl-ethyl)-piperazin-1-yl]-1-(4chloro-benzyl)-2-oxo-ethyl]-amidedi(trifluoroacetate) salt

[1480] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA12 and the BCdomain combination of Preparation BC1. MS m/z 594.3 (M⁺+1)

EXAMPLE N12

[1481]

[1482] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-[1-cyclohexylmethyl-2-methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amidedi(trifluoroacetate) salt

[1483] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA24 and the BCdomain combination of Preparation BC1. MS m/z 644.3 (M⁺+1)

EXAMPLE N13

[1484]

[1485] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-[1-cyclohexylmethyl-2-morpholin-4-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amidetri (trifluoroacetate) salt

[1486] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA23 and the BCdomain combination of Preparation BC1. MS m/z 636.4 (M⁺+1)

EXAMPLE N14

[1487]

[1488] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-[1-cyclohexylmethyl-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amidetri (trifluoroacetate) salt

[1489] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA21 and the BCdomain combination of Preparation BC1. MS m/z 620.4 (M⁺+1)

EXAMPLE N15

[1490]

[1491] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-[1-cyclohexylmethyl-2-piperidin-1-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amidetri (trifluoroacetate) salt

[1492] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA22 and from theBC domain combination of Preparation BC1. MS m/z 634.4 (M⁺+1)(Enantiomer A) and from the BC domain combination of Preparation BC2. MSm/z 650.4 (M⁺+1)

EXAMPLE N16

[1493]

[1494]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidetri(trifluoroacetate) salt

[1495] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA6 and from theBC domain combination of Preparation BC2. MS m/z 608.4 (M⁺+1)

EXAMPLE N17

[1496]

[1497] N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidetrihydrochloride salt

[1498] A mixture of the A domain compound of preparation NA6 (Isomer 1of Method A) (441 mg, 1.17 mmol, 1 eq.), the BC domain combination ofPreparation BC2 (644 mg, 1.40 mmol, 1.2 eq.), HOAT (199 mg, 1.46 mmol,1.25 eq.), HATU (555 mg, 1.46 mmol, 1.25 eq.) and DIPEA (2.03 mL, 11.7mmol, 10 eq.) was stirred in CH₂Cl₂/DMF (4:1, v:v) (7.5 mL) at roomtemperature overnight. Reaction mixture was diluted with water andaqueous layer was extracted with CH₂Cl₂. Combined organic layers weredried (MgSO₄), filtered and concentrated to give a crude product thatwas purified by column chromatography. A solution of the N-BOC protectedproduct in CH₂Cl₂/TFA (1:1, v:v) was stirred at room temperature for 30min. Solvent was evaporated and residue washed with Et₂O and taken into0.1N HCl (10 eq.). Solution was solidified at −78° C. and the solidlyophilized to afford the title compound (331 mg) . MS m/z 608.4 (M⁺+1).

EXAMPLE N18

[1499]

[1500]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidetrihydrochloride salt

[1501] According to the procedure described in Example N17, thiscompound was prepared from the A domain of preparation NA6 (Isomer 2 ofMethod A) and from the BC domain combination of Preparation BC2. MS m/z608.4 (M⁺+1)

EXAMPLE N19

[1502]

[1503]N-{1-(4-chloro-bezyl)-2-{4-[1-cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedihydrochloride salt

[1504] According to the procedure described in Example N17, thiscompound was prepared from the racemic A domain of preparation NA8 andfrom the BC domain combination of Preparation BC2. MS m/z 658.3 (M⁺+1)

EXAMPLE N20

[1505]

[1506]N-{1-(4-chloro-benzyl)-2-{4-[1-cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedihydrochloride salt

[1507] According to the procedure described in Example N17, thiscompound was prepared from the A domain of prepration A8 (Isomer 1 ofMethod A) and from the BC domain combination of Preparation BC2. MS m/z658.3 (M⁺+1)

EXAMPLE N21

[1508]

[1509]N-{1-(4-chloro-benzyl)-2-{4-[1-cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-2H-isoindol-1-yl)-acetamidedihydrochloride salt

[1510] According to the procedure described in Example N17, thiscompound was prepared from the A domain of preparation NA8 (Isomer 2 ofMethod A) and from the BC domain combination of Preparation BC2. MS m/z658.3 (M⁺+1)

EXAMPLE N22

[1511]

[1512]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedi(trifluoroacetate) salt

[1513] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of preparation NA7 and from theBC domain combination of Preparation BC2. MS m/z 630.3 (M⁺+1)

EXAMPLE N23

[1514]

[1515]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedi(trifluoroacetate) salt

[1516] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA7 (Enantiomer Aof Method B) and from the BC domain combination of Preparation BC2. MSm/z 630.3 (M⁺+1)

EXAMPLE 24

[1517]

[1518]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedi(trifluoroacetate) salt

[1519] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA7 (Enantiomer Bof Method B) and from the BC domain combination of Preparation BC2. MSm/z 658.3 (M⁺+1)

EXAMPLE N25

[1520]

[1521]N-[2-{4-(Acethyl-ethyl-amino)-1-cyclohexyl-ethyl]-piperazin-1-yl}-1-(4-chloro-benzyl)-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedi(trifluoroacetate) salt According to the procedure described inExample N1, this compound was prepared from the racemic A domain ofPreparation NA13 and from the BC domain combination of Preparation BC2.MS m/z 622.4 (M⁺+1)

EXAMPLE N26

[1522]

[1523]N-[2-{4-(Acethyl-ethyl-amino)-1-cyclohexyl-ethyl]-piperazin-1-yl}-1-(4-chloro-benzyl)-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedihydrochloride salt

[1524] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA13 (EnantiomerA) and from the BC domain combination of Preparation BC2. MS m/z 622.4(M⁺+1)

EXAMPLE N27

[1525]

[1526]N-[2-{4-(Acethyl-ethyl-amino)-1-cyclohexyl-ethyl]-piperazin-1-yl}-1-(4-chloro-benzyl)-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1yl)-acetamidedihydrochloride salt

[1527] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA13 (EnantiomerB) and from the BC domain combination of Preparation BC2. MS m/z 622.4(M⁺+1)

EXAMPLE N28

[1528]

[1529]N-(1-(4-chloro-benzyl)2-{4-[1-cyclohexyl-2-(2,5-dioxo-pyrrolidin-yl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedi(trifluoroacetate) salt

[1530] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA15 and from theBC domain combination of Preparation BC2. MS m/z 634.3 (M⁺+1)

EXAMPLE N29

[1531]

[1532]N-(1-(4-chloro-benzyl)2-{4-[1-cyclohexyl-2-(2,5-dioxo-pyrrolidin-yl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedihydrochloride salt

[1533] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation of A15(Enantiomer A of Method B) and from the BC domain combination ofPreparation BC2. MS m/z 634.3 (M⁺+1)

EXAMPLE N30

[1534]

[1535]N-(1-(4-chloro-benzyl)2-{4-[1-cyclohexyl-2-(2,5-dioxo-pyrrolidin-yl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamxidedihydrochloride salt

[1536] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA15 (EnantiomerB of Method B) and from the BC domain combination of Preparation BC2. MSm/z 634.3 (M⁺+1)

EXAMPLE N31

[1537]

[1538]N-(1-(4-chloro-benzyl)2-{4-[1-cyclohexyl-2-(2-oxo-pyrrolidin-yl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedihydrochloride salt

[1539] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA14 (EnantiomerA) and from the BC domain combination of Preparation BC2. MS m/z 620.2(M⁺+1)

EXAMPLE N32

[1540]

[1541]N-(1-(4-chloro-benzyl)2-{4-[1-cyclohexyl-2-(2-oxo-pyrrolidin-yl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedihydrochloride salt

[1542] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA14 (EnantiomerB) and from the BC domain combination of Preparation BC2. MS m/z 620.2(M⁺+1)

EXAMPLE N33

[1543]

[1544]2-{4-[3-(4-Chloro-benzyl)2-(2-2,3-dihydro-1H-isoindol-1-yl-acetylamino)-propionyl]-piperazin-1-yl}-3-cyclohexyl-N,N-diethyl-propionamidedi(trifluoroacetate) salt

[1545] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA16 and from theBC domain combination of Preparation BC2. MS m/z 622.4 (M⁺+1)

EXAMPLE N34

[1546]

[1547]2-{4-[3-(4-Chloro-benzyl)2-(2-2,3-dihydro-1H-isoindol-1-yl-acetylamino)-propionyl]-piperazin-1-yl}-3-cyclohexyl-N,N-diethyl-propionamidedihydrochloride salt

[1548] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA16 (EnantiomerA) and from the BC domain combination of Preparation BC2. MS m/z 622.4(M⁺+1)

EXAMPLE N35

[1549]

[1550]2-{4-[3-(4-Chloro-benzyl)2-(2-2,3-dihydro-1H-isoindol-1-yl-acetylamino)-propionyl]-piperazin-1-yl}-3-cyclohexy-N,N-diethyl-propionamidedihydrochloride salt

[1551] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA16 (EnantiomerB) and from the BC domain combination of Preparation BC2. MS m/z 622.4(M⁺+1)

EXAMPLE N36

[1552]

[1553]N-(1-(4-chloro-benzyl)2-[4-(1-cyclohexyl-2-oxo-2-pyrrolidin-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedi(trifluoroacetate) salt

[1554] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA17 and from theBC domain combination of Preparation BC2. MS m/z 620.4 (M⁺+1)

EXAMPLE N37

[1555]

[1556]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexylmethyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidetri(trifluoroacetate) salt According to the procedure described inExample N1, this compound was prepared from the racemic A domain ofPreparation NA20 and from the EC domain combination of Preparation BC2.MS m/z 622.4 (M⁺+1)

EXAMPLE N38

[1557]

[1558]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexylmethyl-2-morpholine-4-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidetri(trifluoroacetate) salt

[1559] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA23 and from theBC domain combination of Preparation BC2. MS m/z 636.4 (M⁺+1)

EXAMPLE N39

[1560]

[1561]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexylmethLyl-2-piperidin-1-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidetri(trifluoroacetate) salt

[1562] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA22 and from theBC domain combination of Preparation BC2. MS m/z 634.4 (M⁺+1)

EXAMPLE N40

[1563]

[1564]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexylmethyl-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidetri(trifluoroacetate) salt

[1565] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA21 and from theBC domain combination of Preparation BC2. MS m/z 620.4 (M⁺+1)

EXAMPLE N41

[1566]

[1567]N-{1-(4-chloro-benzyl)-2-(4-[1-cyclohexylmethyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamnidedihydrochloride salt

[1568] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA25 and from theBC domain combination of Preparation BC2. MS m/z 672.3 (M⁺+1)

EXAMPLE N42

[1569]

[1570]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexylmethyl-2-methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedi(trifluoroacetate) salt

[1571] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA24 and from theBC domain combination of Preparation BC2. MS m/z 644.4 (M⁺+1)

EXAMPLE N43

[1572]

[1573]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamidetri(trifluoroacetate) salt

[1574] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA6 and from theBC domain combination of Preparation BCl3. MS m/z 622.4 (M⁺+1).

EXAMPLE N44

[1575]

[1576]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetanidetri(trifluoroacetate) salt

[1577] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA6 and from theBC domain combination of Preparation BC12. MS m/z 622.4 (M⁺+1)

EXAMPLE N45

[1578]

[1579]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2-methyl-2,3-dihydro-1H-isoindol-1-yl)-acetamidetri(trifluoroaceate) salt

[1580] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA6 and from theBC domain combination of Preparation BC14. MS m/z 622.4 (M⁺+1)

EXAMPLE N46

[1581]

[1582] 1,1-Dimethyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amidetrihydrochloride salt

[1583] According to the procedure described in Example N17, thiscompound was prepared from the racemic A domain of Preparation NA6 andfrom the EC domain combination of Preparation BC11 (Diastereomer 1). MSm/z 636.2 (M⁺+1)

EXAMPLE N47

[1584]

[1585] 1,1-Dimethyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-diethylanino-ethyl)-piperazin-1-yl]-2-oxo-ethyl)-amidetrihydrochloride salt

[1586] According to the procedure described in Example N17, thiscompound was prepared from the racemic A domain of Preparation NA6 andfrom the BC domain combination of Preparation BC11 (Diastereomer 2). MSm/z 636.2 (M⁺+1)

EXAMPLE N48

[1587]

[1588] Isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amidedihydrochloride salt

[1589] According to the procedure described in Example N3, this compoundwas prepared from the A domain of Preparation NA6 (Enantiomer B MethodB) and from the BC domain combination of Preparation BC15. MS m/z 604.3(M⁺+1)

EXAMPLE N49

[1590]

[1591]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl]-2oxo-ethyl}-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamidedi(trifluoroacetate) salt

[1592] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA8 and from theBC domain combination of Preparation BC12. MS m/z 672.3 (M⁺+1)

EXAMPLE 50

[1593]

[1594]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl]-2-oxo-ethyl}-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamidedi(trifluoroacetate) salt

[1595] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA8 and from theBC domain combination of Preparation BC13. MS m/z 672.3 (M⁺+1)

EXAMPLE N51

[1596]

[1597]N-{1-(4-chloro-benzyl)-2-{4-[1-cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2-methyl-2,3-dihydro-1H-isoindol-1-yl)-acetamidedi(trifluoroacetate) salt

[1598] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA8 and from theBC domain combination of Preparation BC14. MS m/z 672.3 (M⁺+1)

EXAMPLE N52

[1599]

[1600] Isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-{4-[1-cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl}-amide

[1601] A mixture of the racemic A domain compound of Preparation NA8 (1eq.), the BC domain combination of Preparation BC15 (1.2 eq.), HOAT(1.25 eq.), HATU (1.25 eq.) and DIPEA (10 eq.) was stirred in CH₂Cl₂/DMF(4:1, v:v) at room temperature overnight. Reaction mixture was dilutedwith water and aqueous layer was extracted with CH₂Cl₂. Combined organiclayers were dried (MgSO₄), filtered and concentrated to give a crudeproduct that was purified by column chromatography. MS m/z 654.2 (M⁺+1)

EXAMPLE N53

[1602]

[1603] 1,1-Dimethyl-1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[1-cyclohexylmethyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amidedihydrochloride salt

[1604] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA8 (Enantiomer Bof Method B) and from the BC domain combination of Preparation BC11(Diasteromer 2). MS m/z 686.3 (M⁺+1)

EXAMPLE N54

[1605]

[1606] 1,1-Dinethyl-1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[1-cyclohexylmethyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amidedihydrochloride salt

[1607] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA8 (Enantiomer Aof Method B) and from the BC domain combination of Preparation BC11(Diasteromer 1). MS m/z 686.3 (M⁺+1)

EXAMPLE N55

[1608]

[1609] 1,1-Dimethyl-1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[1-cyclohexylmethyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amidedihydrochloride salt

[1610] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA8 (Enantiomer Bof Method 3) and from the BC domain combination of Preparation BC11(Diasteromer 1). MS m/z 686.3 (M⁺+1)

EXAMPLE N56

[1611]

[1612]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-methanesulfonyl-amino-ethyl]-piperazin-1-yl]-2-oxo-ethyl}-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamidedi(trifluoroacetate) salt

[1613] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA7 and from theBC domain combination of Preparation BC12. MS m/z 644.3 (M⁺+1)

EXAMPLE N57

[1614]

[1615]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-methanesulfonyl-amino-ethyl]-piperazin-1-yl]-2-oxo-ethyl}-2-(1,2,3,4tetrahydro-isoquinolin-1-yl)-acetamidedi(trifluoroacetate) salt

[1616] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA7 and from theBC domain combination of Preparation BC13 (Diasteromer 2). MS m/Z 644.3(M⁺+1)

EXAMPLE N58

[1617]

[1618]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-methanesulfonyl-amino-ethyl]-piperazin-1-yl]-2-oxo-ethyl}-2-(1,2,3.4-tetrahydro-isoquinolin-1-yl)-acetamidedi(trifluoroacetate) salt

[1619] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA7 (Enantiomer Aof Method B) and from the BC domain combination of Preparation BC13. MSm/z 644.3 (M⁺+1)

EXAMPLE N59

[1620]

[1621]N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-methanesulfonyl-amino-ethyl]-piperazin-1-yl]-2-oxo-ethyl}-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamidedi(trifluoroacetate) salt

[1622] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA7 (Enantiomer Bof Method B) and from the BC domain combination of Preparation BC13. MSm/z 644.3 (M⁺+1)

EXAMPLE N60

[1623]

[1624]N-{1-(4-chloro-benzyl)-2-{4-[1-cyclohexyl-2-methanesulfonyl-amino-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2-methyl-2,3-dihydro-1H-isoindol-1-yl)-acetamidedi(trifluoroacetate) salt

[1625] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of Preparation NA7 and from theBC domain combination of Preparation BC14. MS m/z 644.3 (M⁺+1)

EXAMPLE N61

[1626]

[1627] 1,1-Dimethyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-[1-cyclohexyl-2-methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide dihydrochloride salt

[1628] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA7 (Enantiomer Aof Method B) and from the BC domain combination of Preparation BC11(Diasteromer 1). MS m/z 658.3 (M⁺+1)

EXAMPLE N62

[1629]

[1630] 1,1-Dimethyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-[1-cyclohexyl-2-methanesulfonylnio-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amidedihydrochloride salt

[1631] According to the procedure described in Example N21, thiscompound was prepared from the A domain of Preparation NA7 (Enantiomer Bof Method B) and from the BC domain combination of Preparation BC11(Diasteromer 1). MS m/z 658.3 (M⁺+1)

EXAMPLE N63

[1632]

[1633] 1,1-Dimethyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-[1-cyclohexyl-2-methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}amidedihydrochloride salt

[1634] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA7 (Enantiomer Aof Method B) and from the BC domain combination of Preparation BC11(Diasteromer 2). MS m/z 658.3 (M⁺+1)

EXAMPLE N64

[1635]

[1636] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-(1-diethylamino-1-phenyl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amidetrihydrochloride salt

[1637] According to the procedure described in Example N3, this compoundwas prepared from the A domain of Preparation NA33 and from the BCdomain combination of Preparation BC1. MS m/z 602.3 (M⁺+1)

EXAMPLE N65

[1638]

[1639] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-(1-diethylamino-1-phenyl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amidetrihydrochloride salt

[1640] According to the procedure described in Example N3, this compoundwas prepared from the A domain of Preparation NA34 and from the BCdomain combination of Preparation BC1. MS m/z 602.3 (M⁺+1)

EXAMPLE N66

[1641]

[1642] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid[2-[4-(1-benzyl-2-diethylamino-ethyl)-piperazin-1-yl]-1-(4-chloro-benzyl)-2-oxo-ethyl]-amidetrihydrochloride salt

[1643] According to the procedure described in Example N3, this compoundwas prepared from the racemic A domain of Preparation NA37 and from theBC domain combination of Preparation BC1. MS m/z 616.3 (M⁺+1)

EXAMPLE N67

[1644]

[1645] 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-(2-diethylamino-1-pyridin-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amidetetrahydrochloride salt

[1646] According to the procedure described in Example N1, this compoundwas prepared from the racemic A domain of preparation NA38 and from theBC domain combination of Preparation BC1. MS m/z 603.6 (M⁺+1)

EXAMPLE N68

[1647]

[1648]N-{1-(4-Chloro-benzyl)-2-[4-(1-cyclohexyl-3-methyl-but-2-enyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedihydrochloride salt.

[1649] According to the procedure described in Example N17, thiscompound was prepared from the racemic A domain of preparation NA39 andfrom the BC domain combination of Preparation BC2. MS m/z 577.3 (M⁺+1)

EXAMPLE N69

[1650]

[1651]N-{1-(4-Chloro-benzyl)-2-[4-(1-cyclohexyl-3-methyl-butyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3dihydro-1H-isoindol-1-yl)-acetamidedihydrochloride salt

[1652] According to the procedure described in Example N17, thiscompound was prepared from the racemic A domain of preparation NA40 andfrom the BC domain combination of Preparation BC2. MS m/z 579.4 (M⁺+1)

EXAMPLE N70

[1653]

[1654]N-{1-(4-Chloro-benzyl)-2-[4-(2-cyclohexyl-1-cyclohexylmethyl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedihydrochloride salt

[1655] According to the procedure described in Example N17, thiscompound was prepared from the A domain of preparation NA41 and from theBC domain combination of Preparation BC2. MS m/z 633.4 (M⁺+1)

EXAMPLE N71

[1656]

[1657]N-(1-(4-Chloro-benzyl)-2-{4-[1-cyclohexyl-2-(isobutyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedihydrochloride salt

[1658] According to the procedure described in Example N17, thiscompound was prepared from the A domain of preparation NA42 (EnantiomerA) and from the BC domain combination of Preparation BC2. MS m/z 686.3(M⁺+1)

EXAMPLE N72

[1659]

[1660]N-(1-(4-Chloro-benzyl)-2-{4-[1-cyclohexyl-2-(isobutyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedihydrochloride salt

[1661] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA42 (EnantiomerB) and from the BC domain combination of Preparation BC2. MS m/z 686.3(M⁺+1)

EXAMPLE N73

[1662]

[1663]N-[2-{4-[2-(Acetyl-isobutyi-amino)-1-cyclohexyl-ethyl]-piperazin-1-yl}-1-(4-chloro-benzyl)-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedihydrochloride salt

[1664] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA43 (EnantiomerA) and from the BC domain combination of Preparation BC2. MS m/z 650.4(M⁺+1)

EXAMPLE N74

[1665]

[1666]N-[2-{4-[2-(Acetyl-isobutyl-amino)-1-cyclohexyl-ethyl]-piperazin-1-yl}-1-(4-chloro-benzyl)-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedihydrochloride salt

[1667] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA43 (EnantiomerB) and from the BC domain combination of Preparation BC2. MS m/z 650.4(M⁺+1)

EXAMPLE N75

[1668]

[1669]N-[1-(4-Chloro-benzyl)-2-(4-dicyclohexylmethyl-piperazin-1-yl)-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamidedihydrochloride salt.

[1670] According to the procedure described in Example N17, thiscompound was prepared from the A domain of Preparation NA44 and from theBC domain combination of Preparation BC2. MS m/z 605.3 (M⁺+1)

EXAMPLE 76

[1671]

[1672] Isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amidedihydrochloride salt

[1673] A mixture of the racemic A domain compound of Preparation A6(Enantiomer A, Method B) (1 eq.), the BC domain combination of exampleBC15 (1.2 eq.), HOAT (1.25 eq.), HATU (1.25 eq.) and DIPEA (10 eq.) wasstirred in CH₂Cl₂/DMF (4:1, v:v) at room temperature overnight.Extractive work up with EtOAc yielded the crude product that waspurified by column chromatography. A solution of the N-Boc protectedproduct in 1N HCl/EtOAc was stirred at room overnight. Solvent wasevaporated and residue washed with Et₂O to afford the title compound(79%). MS m/z 604.3 (M⁺+1).

EXAMPLE 77

[1674]

[1675] Isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-diethylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amidedihydrochloride salt

[1676] According to the procedure described in Example N76, thiscompound was prepared from the A domain of Preparation A6 (Enantiomer B,Method B) and from the BC domain combination of Example BC15. MS m/z604.3 (M⁺+1)

EXAMPLE N78

[1677]

[1678] Isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-{4-[1-cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl}-amide

[1679] A mixture of the racemic A domain compound of Preparation A8 (1eq.), the BC domain combination of example BC15 (1.2 eq.), HOAT (1.25eq.) HATU (1.25 eq.) and DIPEA (10 eq.) was stirred in CH₂Cl₂/DMF (4:1,v:v) at room temperature overnight. Reaction mixture was diluted withwater and aqueous layer was extracted with CH₂Cl₂. Combined organiclayers were dried (MgSO₄), filtered and concentrated to give a crudeproduct that was purified by column chromatography. MS m/z 654.2 (M⁺+1)

EXAMPLE 79

[1680]

[1681] Isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-{4-[1-cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl}-amide

[1682] According to the procedure described in Example N78, thiscompound was prepared from the A domain of Preparation A7 and from theBC domain combination of Example BC15. MS m/z 626.0 (M⁺+1)

EXAMPLE N80

[1683]

[1684] Isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide

[1685] To the “A-B” piece (Compound #707, Table XIV) (1 eq.), thecommercially available isoquinoline-3-carboxylic acid hydrate (1 eq.),EDC (1 eq.) and HOBT (1 eq.) was added MeCl₂ (to make the a 0.5 Msolution). NMM (3 eq.) was then added and the reaction was allowed tostir at room temperature for 4 h. The reaction mixture was thenconcentrated to dryness. The resulting reside was taken up in EtOAc andwashed with sat. NaHCO₃ and brine. The organic phase was collected andconcentrated to dryness. The crude material was further purified bycolumn chromatography (silica gel 60 mesh, eluting with a gradient of100% EtOAc to 5% MeOH/5% TEA in EtOAc) yielding the pure free base ofthe title compound at a yield of 80%. The HCl salt of the title compoundcan be obtained by taking the free base up in 1N HCl and lyophillizingovernight. MS (ES) 616.3 [M+1]

EXAMPLE 81

[1686]

[1687] Isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[diethylcarbamoyl-(2,4-difluoro-phenyl)-methyl]-piperazin-1-yl}-2-oxo-ethyl)-amide

[1688] According to the procedure described in Example 80, the titlecompound was prepared from the “A-B” piece (compound of Preparation G8)and the commercially available isoquinoline-3-carboxylic acid hydrate.

[1689] MS (ES) 648.3 [M+1]

1. A compound of formula I

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,wherein L and L¹ are both hydrogen, or combine together to form an oxogroup; R² is: Hydrogen, C₁-C₈ alkyl, CONHC₁-C₄ alkyl, (D)phenyl, oxo, or(D)C₃-C₇ cycloalkyl, provided that when R² is oxo, R² is on one of thering carbon atoms adjacent to Q bearing nitrogen atom; R³ is: phenyl,aryl or thienyl; wherein phenyl, aryl and thienyl are optionallysubstituted with one to three substituents independently selected fromthe group consisting of: cyano, perfluoroalkoxy, halo, C₁-C₈ alkyl,(D)C₃-C₇ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl; R⁴ is hydrogen,C₁-C₈ alkyl, C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl, or (D)phenyl; Q is:—C(R^(a1)) (R^(a2)) (R^(a3)) Wherein R^(a1) is C₁-C₈ alkyl, C₁-C₈alkenyl, C₁-C₈ alkynyl, C₃-C₈ alkoxy, (D)C₃-C₇ cycloalkyl, heterocyclic,alky1 heterocyclic, (D)phenyl, aryl, 5 to 7 member benzofused bicyclicring, or heteroaryl, and wherein C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈alkynyl, (D)C₃-C₇ cycloalkyl, heterocyclic, alkyl heterocyclic, phenyl,aryl, 5- or 7-membered benzofused bicyclic ring, and heteroaryl, areeach optionally substituted with one to five substituents independentlyselected from R; R is: hydroxy, halo, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈alkoxy, C₁-C₄ haloalkyl, (D)C₃-C₇ cycloalkyl, (D)aryl, (D)heteroaryl;(D)C(O)C₁-C₄ alkyl, (D)C(O)OC₁-C₄ alkyl, (D)C(O)heteroaryl,(CH₂)_(m)N(R⁸ )₂, (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl, (CH₂)_(m)NR⁸SO₂(C₁-C₄alkyl), (D)OC₁-C₄ alkyl, (D)OC(O)C₁-C₄ alkyl, (D)heterocyclic, (D)SC₁-C₄alkyl, or (D)SO₂N(R⁸)₂; wherein C₁-C₈ alkyl, C₁-C₈ alkoxy, C₃-C₇cycloalkyl, phenyl, aryl, heterocyclic, and heteroaryl are optionallysubstituted with one to five substituents independently selected fromR⁸; and provided that when R is halo or hydroxy it is not substituted ona carbon adjacent to a heteroatom; R^(a2) is C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, (D)C₃-C₇ cycloalkyl, phenyl, aryl, (CH₂)_(m)N(R⁸)₂,(CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl, (CH₂)_(m)NR⁸C(O)OC₁-C₄ alkyl,(CH₂)_(m)NR⁸SO₂(C₁-C₄ alkyl), (CH₂)_(m)OC₁-C₄ alkyl, (CH₂)_(m)OC(O)C₁-C₄alkyl, CON(R⁸)₂, wherein for the group or subgroup —N(R⁸)₂, each R⁸ maycombine with the other to form a 5, 6, or 7-membered saturated orunsaturated, optionally substituted nitrogen containing heterocycle;R^(a3) is selected from the group consisting of hydrogen, methyl, ethyland propyl; each R⁸ is independently: hydrogen, oxo, C₁-C₈ alkyl, C₂-C₈alkenyl, (D)C₃-C₇ cycloalkyl, phenyl, aryl or heteroaryl, wherein C₁-C₈alkyl, C₁-C₈ alkenyl, C₃-C₇ cycloalkyl, phenyl, aryl and heteroaryl areoptionally substituted with one to three substituents selected from thegroup consisting of C₁-C₈ alkyl, halo, and hydroxy; provided that thehalo and hydroxy groups are not substituted on a carbon adjacent to aheteroatom; T is:

R¹⁰ is hydrogen, (C₁-C₈)alkyl, C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl, C₂-C₈alkynyl, phenyl, aryl, or heteroaryl; R¹¹ is independently hydrogen,(C₁-C₈)alkyl, or (D)phenyl, or axyl; R¹² is independently: C₁-C₁₈ alkyl,phenyl, aryl, heteroaryl, (CH₂)_(n)N(R⁸)₂, (CH₂)_(n)NR⁸C(O)C₁-C₄ alkyl,(CH₂)_(n)NR⁸C(O)OC₁-C₄ alkyl, (CH₂)_(n)[O]_(q)(CH₂)_(n)N(R⁸)₂,(CH₂)_(n)[O]_(q)(CH₂)_(n)NR⁸C(O)C₁-C₄ alkyl,(CH₂)_(n)[O]_(q)(CH₂)_(n)NR⁸SO₂(C₁-C₄ alkyl),(CH₂)_(n)[O]_(q)-heterocyclic,(CH₂)_(n)[O]_(q)(C₁-C₈)alkyl-heterocyclic; and wherein for R¹² n is 2-8;R¹³ is independently: hydrogen, C₁-C₈ alkyl, (D)C₃-C₇ cycloalkyl,(D)phenyl, C(O)C₁-C₈ alkyl, SO₂C₁-C₈ alkyl, or SO₂-phenyl; D is a bondor C₁-C₄ alkyl; y is 1 or 2; m is 1-4; n is 0-8; p is 0-4; and q is 0-1.2. A compound of formula II:

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,wherein L and L¹ are both hydrogen, or combine together to form an oxogroup; R¹ is selected from the group consisting of: Hydrogen, Halo,C₁-C₈ alkyl, C₁-C₄ haloalkyl C₂-C₈ alkenyl, C₂-C₈ alkynyl, (D)C₃-C₇cycloalkyl, phenyl, aryl, (D)N(R⁸)₂, (D)NR⁸C(O)C₁-C₄ alkyl,(D)NR⁸C(O)OC₁-C₄ alkyl, (D)OC₁-C₄ alkyl, wherein for the group orsubgroup —N(R⁸)₂, each R⁸ may combine with the other to form a 5, 6, or7-membered saturated or unsaturated, optionally substituted nitrogencontaining heterocycle; R² is: Hydrogen, C₁-C₈ alkyl, CONHC₁-C₄ alkyl,(D)phenyl, oxo, or (D)C₃-C₇ cycloalkyl, provided that when R² is oxo, R²is on one of the ring carbon atoms adjacent to the nitrogen atom bearingthe group CR^(a2); R^(3′) is: phenyl, aryl; wherein phenyl, and aryl areeach optionally substituted with one to three substituents independentlyselected from the group consisting of: cyano, halo, C₁-C₈ alkyl,(D)C₃-C₇ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl and perfluoroalkoxy;R⁴ is hydrogen, C₁-C₈ alkyl, C₃-C₈ alkenyl, or (D)phenyl; R^(a2) is:C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, (D)C₃-C₇ cycloalkyl, phenyl,aryl, (CH₂)_(m)N(R⁸)₂, (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl,(CH₂)_(m)NR⁸C(O)OC₁-C₄ alkyl, (CH₂)_(m)NR⁸SO₂(C₁-C₄ alkyl),(CH₂)_(m)OC₁-C₄ alkyl, (CH₂)_(m)OC(O)C₁-C₄ alkyl, CON(R⁸)₂, wherein forthe group or subgroup —N(R⁸)₂, each R⁸ may combine with the other toform a 4, 5, 6, or 7-membered saturated or unsaturated, optionallysubstituted nitrogen containing heterocycle; R^(a3) is selected from thegroup consisting of hydrogen, methyl, ethyl and propyl; T′ is:

R is: hydroxy, halo, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈ alkoxy, C₁-C₄haloalkyl, (D)C₃-C₇ cycloalkyl, (D)aryl, (D)heteroaryl; (D)C(O)C₁-C₄alkyl, (D)C(O)OC₁-C₄ alkyl, (D)C(O)heteroaryl, (CH₂)_(m)N(R⁸)₂,(CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl, (CH₂)_(m)N⁸SO₂(C₁-C₄ alkyl), (D)OC₁-C₄alkyl, (D)OC(O)C₁-C₄ alkyl, (D)heterocyclic, (D)SC₁-C₄ alkyl, or(D)SO₂N(R⁸)₂; wherein C₁-C₈ alkyl, C₁-C₈ alkoxy, C₃-C₇ cycloalkyl,phenyl, aryl, heterocyclic, and heteroaryl are optionally substitutedwith one to five substituents independently selected from R⁸; andprovided that when R is halo or hydroxy it is not substituted on acarbon adjacent to a heteroatom; each R⁸ is independently: hydrogen,oxo, C₁-C₈ alkyl, C₂-C₈ alkenyl, (D)C₃-C₇ cycloalkyl, phenyl, aryl orheteroaryl, wherein C₁-C₈ alkyl, C₁-C₈ alkenyl, C₃-C₇ cycloalkyl,phenyl, aryl and heteroaryl are optionally substituted with one to threesubstituents selected from the group consisting of C₁-C₈ alkyl, halo,and hydroxy; provided that the halo and hydroxy groups are notsubstituted on a carbon adjacent to a heteroatom; R¹⁰ is hydrogen,(C₁-C₈)alkyl, C₃-C₈ alkenyl, C₂-C₈ alkynyl, phenyl, aryl, or heteroaryl;R¹¹ is independently hydrogen, (C₁-C₈)alkyl, or phenyl, aryl; R¹² isindependently: C₁-C₈ alkyl, phenyl, aryl, heteroaryl, (CH₂)_(n)N(R⁸)₂,(CH₂)_(n)NR⁸C(O)C₁-C₄ alkyl, (CH₂)_(n)NR⁸C(O)OC₁-C₄ alkyl,(CH₂)_(n)[O]_(q)(CH₂)_(n)N(R⁸)₂, (CH₂)_(n)[O]_(q)(CH₂)_(n)NR⁸C(O)C₁-C₄alkyl, (CH₂)_(n)[O]_(q)(CH₂)_(n)NR⁸SO₂(C₁-C₄ alkyl),(CH₂)_(n)[O]_(q)-heterocyclic,(CH₂)_(n)[O]_(q)(C₁-C₈)alkyl-heterocyclic; and wherein for R¹² n is 2-8;R¹³ is independently: hydrogen, C₁-C₈ alkyl, (D)C₃-C₇ cycloalkyl,(D)phenyl, C(O)C₁-C₈ alkyl, SO₂C₁-C₈ alkyl, or SO₂-phenyl; D is a bondor C₁-C₄ alkyl; y is 1 or 2; u is 0, 1, or 2; m is 1-4; n is 0-8; p is0-4; and q is 0-1.
 3. The compound of claim 1, wherein the C₃-C₇cycloalkyl is cyclohexyl, cyclopentyl, or cycloheptane.
 4. The compoundof claim 1, wherein the heterocyclyl is 5- or 6-membered ring containingat least one nitrogen and 0 to 3 atoms selected from O, or S wherein thenitrogen is substituted with a substituent selected from the groupconsisting of hydrogen, C₁-C₈ alkyl, C₃-C₇ cycloalkyl, phenyl and benzyl5. The compound of claim 1, wherein the heterocyclyl is piperidinyl,pyrrolidinyl, pyrrolinyl, isoxazolyl, oxazolyl, thiazoyl, triazolyl,tetrazolyl, thiadiazolyl, or oxadiazolyl.
 6. The compound of claim 1,wherein R is independently at each occurrence: hydrogen, C₁-C₈ alkyl,C₁-C₈ alkoxy, C₃-C₇ cycloalkyl, (D)heterocyclyl, (D)C(O)aryl,C(O)N(R⁸)₂, (D)N(R⁸)₂, where R⁸ independently at each occurrence ishydrogen, C₁-C₈ alkyl, or phenyl.
 7. The compound of claim 1 or 2,wherein R³ is phenyl optionally para-substituted with chloro, bromo,benzyloxy or methyl.
 8. The compound of claim 1 or 2, wherein R³ isphenyl para-substituted with chloro.
 9. The compound of claim 8, whereinR⁴ is hydrogen.
 10. The compound of claim 1, wherein T is

where * denotes a chiral carbon atom which has a R or S configuration.11. The compound of any one of claims 1 or 2 wherein T is a moiety ofthe formula:

wherein R′ is H or OH; and wherein the carbon atom marked * is chiral.12. The compound of any one of claims 1 or 2 wherein L and L¹ are eachhydrogen; and T is a moiety of the formula:


13. The compound of claim 10 or 11 wherein the carbon atom marked with *has the R or S configuration.
 14. A compound according to claim 2wherein T′ is selected from the group consisting of:

where * denotes a chiral carbon atom which has a R or S configuration.15. A compound according to claim 1 or 2 or 3 wherein R^(a3) ishydrogen, methyl, ethyl, or propyl.
 16. A compound according to claim 1or 2 or 3 wherein R^(a3) is hydrogen.
 17. A compound according to claim1 wherein T is

R² is Hydrogen, R³ is 4-chlorophenylmethyl, R⁴ is hydrogen, R^(a3) ishydrogen, and R^(a1) is selected from the group consisting of: n-butyl,isobutyl, trifluoromethylphenyl, 4-methylphenyl, cyclopentyl,cyclohexyl, cycloheptyl, 2-fluorophenyl, 2-chlorophenyl, phenyl, andbenzyl.
 18. A compound according to claim 17 wherein R^(a2) is a groupselected from the group consisting of: cyclohexyl, methylcyclohexyl,isopropyl, isobutyl, N-methylmethanesulfonamido, N,N-diethylmethylamino,N-methylpyrrolidinyl, N-benzylmethansulfonylamido, N-methylphthalimido,methylacetamido, N-methylmorpholino, N-methylpiperidinyl,N-methyacetamido, N-methylmaleimido, 2-oxo-N-methylpyrrolidinyl,carboxy-N,N-diethylamino, N-ethylmethanesulfonylamido,N-isobutylmethanesulfonylamido, and N-isobutyl,N-carboxymethylamine. 19.A compound according to claim 1 wherein T is

R² is Hydrogen, R³ is 4-chlorophenylmethyl, R⁴ is hydrogen, R^(a3) ishydrogen, and R^(a1) is selected from the group consisting of: n-butyl,isobutyl, trifluoromethylphenyl, 4-methylphenyl, cyclopentyl,cyclohexyl, cycloheptyl, 2-fluorphenyl, 2-chlorophenyl, phenyl, andbenzyl.
 20. A compound according to claim 19 wherein R^(a2) is a groupselected from the group consisting of:cyclohexyl, methylcyclohexyl,isopropyl, isobutyl, N-methylmethanesulfonamido, N,N-diethylmethylamino,N-methylpyrrolidinyl, N-benzylmethansulfonylamido, N-methylphthalimido,methylacetamido, morpholino, N-methylpiperidinyl, N-methyacetamido,N-methylmaleimido, 2-oxo-N-methylpyrrolidinyl, carboxy-N,N-diethylamino,N-ethylmethanesulfonylamido, N-isobutylmethanesulfonamido, andN-isbutyl,N-carboxymethylamine.
 21. A pharmaceutical compositioncomprising a compound of any one of claims 1-20 and a pharmaceuticalcarrier.
 22. The pharmaceutical composition of claim 21 furthercomprising a second active ingredient selected from the group consistingof an insulin sensitizer, insulin mimetic, sulfonylurea,alpha-glucosidase inhibitor, HMG-CoA reductase inhibitor, sequestrantcholesterol lowering agent, beta 3 adrenergic receptor agonist,neuropeptide Y antagonist, and phosphodiester V inhibitor.
 23. Acompound selected from the group consisting of:

“A” isomer#2 Isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide,

1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1-(2-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide,

1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1-(2,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide,

“A” isomer#2N-(1-(4-Chloro-benzyl)-2-{4-[2-diethylamino-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3dihydro-1H-isoindol-1-yl)-acetamide,

“A” isomer#2N-(1-(4-Chloro-benzyl)-2-(4-[1-(2-chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide,

1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-(2-dipropylamino-1-phenyl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide,

1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide,

“A” isomer #22-{4-[3-(4-Chloro-phenyl)-2-(2-2,3-dihydro-1H-isoindol-1-yl-acetylamino)-propionyl]-piperazin-1-yl}-N,N-diethyl-2-(2-fluoro-phenyl)-acetamide,

N-{1-(4-Chloro-benzyl)-2-[4-(1-isobutyl-3-methyl-butyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide,

N-(1-(4-Chloro-benzyl)-2-{4-[1-cyclohexyl-2-(ethyl-methanesulfonyl-amino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide,

“A” isorner#2, “C” isomner#21,1-Dimethyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[2-diethylamino-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide,

3-(4-Chloro-phenyl)-1-{4-[2-diethylamino-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-[(1,2,3,4-tetrahydro-isoquinolin-3-ylmethyl)-amino]-propan-1-one,

“A” isomer#2, “C” isomer#2N-(1-(4-Chloro-benzyl)-2-{4-[1-(2-chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2-methyl-2,3-dihydro-1H-isoindol-1-yl)-acetamide,

7-Fluoro-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid{1-(4-chloro-benzyl)-2-[4-(2-diethylamino-1-phenyl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-amide,

“A” isomer#2, “C” isomer#2N-(1-(4-Chloro-benzyl)-2-{4-[1-(2-chloro-phenyl)-2-diethylamino-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetamide,

“A” isomer#2, “C” isomer#1N-(1-(4-Chloro-benzyl)-2-{4-[2-diethylamino-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(1-methyl-2,3-dihydro-1H-isoindol-1-yl)-acetamide,

1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid(1-(4-chloro-benzyl)-2-{4-[1-(2-fluoro-phenyl)-2-methanesulfonylamino-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-amide,

“A” isomer#2, “C” isomer#2N-(1-(4-Chloro-benzyl)-2-{4-[2-(ethyl-methanesulfonylamino)-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide,

1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid[2-{4-[2-(acetyl-methyl-amino)-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-1-(4-chloro-benzyl)-2-oxo-ethyl]-amide,

[2-(4-{3-(4-Chloro-phenyl)-2-[(1,2,3,4-tetrahydro-isoquinoline-3-carbonyl)-amino]-propionyl}-piperazin-1-yl)-2-(2-fluoro-phenyl)-ethyl]-ethyl-carbamicacid methyl ester,

N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-diethylaminoethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide,

“C” isomer#2N-{1-(4-chloro-benzyl)-2-[4-(1-cyclohexyl-2-methanesulfonylamino-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide,and

“C” isomer#2N-(1-(4-chloro-benzyl)2-{4-[1-cyclohexyl-2-(2,5-dioxo-pyrrolidin-yl)-ethyl]-piperazin-1-yl}-2-oxo-ethyl]-2-(2,3-dihydro-1H-isoindol-1-yl)-acetamide,and a pharmaceutically acceptable salt, stereoisomer and solvatethereof.
 24. A compound of formula I:

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,wherein L and L¹ are both hydrogen, or combine together to form an oxogroup; R² is: Hydrogen, C₁-C₈ alkyl, CONHC₁-C₄ alkyl, (D)phenyl, oxo, or(D)C₃-C₇ cycloalkyl, provided that when R² is oxo, R² is on one of thering carbon atoms adjacent to Q bearing nitrogen atom; R³ is: phenyl,aryl or thienyl; wherein phenyl, aryl and thienyl are optionallysubstituted with one to three substituents independently selected fromthe group consisting of: cyano, perfluoroalkoxy, halo, C₁-C₈ alkyl,(D)C₃-C₇ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl; R⁴ is hydrogen,C₁-C₈ alkyl, C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl, or (D)phenyl; Q is:—C(R^(a1)) (R^(a2)) (R^(a3)) Wherein R^(a1) is C₁-C₈ alkyl, C₁-C₈alkenyl, C₁-C₈ alkynyl, C₃-C₈ alkoxy, (D)C₃-C₇ cycloalkyl, heterocyclic,alkyl heterocyclic, (D)phenyl, aryl, 5 to 7 member benzofused bicyclicring, or heteroaryl, and wherein C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈alkynyl, (D)C₃-C₇ cycloalkyl, heterocyclic, alkyl heterocyclic, phenyl,aryl, 5- or 7-membered benzofused bicyclic ring, and heteroaryl, areeach optionally substituted with one to five substituents independentlyselected from R; R is: hydroxy, halo, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈alkoxy, C₁-C₄ haloalkyl, (D)C₃-C₇ cycloalkyl, (D)aryl, (D)heteroaryl;(D)C(O)C₁-C₄ alkyl, (D)C(O)OC₁-C₄ alkyl, (D)C(O)heteroaryl,(CH₂)_(m)N(R⁸ )₂, (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl, (CH₂)_(m)NR⁸SO₂(C₁-C₄alkyl), (D)OC₁-C₄ alkyl, (D)OC(O)C₁-C₄ alkyl, (D)heterocyclic, (D)SC₁-C₄alkyl, or (D) SO₂N(R⁸)₂; wherein C₁-C₈ alkyl, C₁-C₈ alkoxy, C₃-C₇cycloalkyl, phenyl, aryl, heterocyclic, and heteroaryl are optionallysubstituted with one to five substituents independently selected fromR⁸; and provided that when R is halo or hydroxy it is not substituted ona carbon adjacent to a heteroatom; R^(a2) is C₁-C₈ alkyl, C₂-C₈ alkenyl,C2-C8 alkynyl, (D)C₃-C₇ cycloalkyl, phenyl, aryl, (CH₂)_(m)N(R⁸)₂,(CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl, (CH₂)_(m)NR⁸C(O)OC₁-C₄ alkyl,(CH₂)_(m)NR⁸SO₂(C₁-C₄ alkyl), (CH₂)_(m)OC₁-C₄ alkyl, (CH₂)_(m)OC(O)C₁-C₄alkyl, CON(R⁸)₂, wherein for the group or subgroup —N(R⁸)₂, each R⁸ maycombine with the other to form a 5, 6, or 7-membered saturated orunsaturated, optionally substituted nitrogen containing heterocycle;R^(a3) is selected from the group consisting of hydrogen, methyl, ethyland propyl; each R⁸ is independently: hydrogen, oxo, C₁-C₈ alkyl; C₂-C₈alkenyl, (D)C₃-C₇ cycloalkyl, phenyl, aryl or heteroaryl, wherein C₁-C₈alkyl, C₁-C₈ alkenyl, C₃-C₇ cycloalkyl, phenyl, aryl and heteroaryl areoptionally substituted with one to three substituents selected from thegroup consisting of C₁-C₈ alkyl, halo, and hydroxy; provided that thehalo and hydroxy groups are not substituted on a carbon adjacent to aheteroatom; T is:

R¹⁰ is hydrogen, (C₁-C₈)alkyl, C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl, C₂-C₈alkynyl, phenyl, aryl, or heteroaryl; R¹¹ is independently hydrogen,(C₁-C₈)alkyl, or (D)phenyl, or aryl; R¹² is independently: C₁-C₈ alkyl,phenyl, aryl, heteroaryl, (CH₂)_(n)N(R⁸)₂, (CH₂)_(n)NR⁸C(O)C₁-C₄ alkyl,(CH₂)_(n)NR⁸C(O)OC₁-C₄ alkyl, (CH₂)_(n)[O]_(q)(CH₂)_(n)N(R⁸)₂,(CH₂)_(n)[O]_(q)(CH₂)_(n)NR⁸C(O)C₁-C₄ alkyl,(CH₂)_(n)[O]_(q)(CH₂)_(n)NR⁸SO₂(C₁-C₄ alkyl),(CH₂)_(n)[O]_(q)-heterocyclic,(CH₂)_(n)[O]_(q)(C₁-C₈)alkyl-heterocyclic; and wherein for R¹² n is 2-8;R¹³ is independently: hydrogen, C₁-C₈ alkyl, (D)C₃-C₇ cycloalkyl,(D)phenyl, C(O)C₁-C₈ alkyl, SO₂C₁-C₈ alkyl, or SO₂-phenyl; D is a bondor C₁-C₄ alkyl; y is 1 or 2; m is 1-4; n is 0-8; p is 0-4; and q is 0-1,useful in the manufacture of a medicament for treating obesity and/ordiabetes.
 25. A pharmaceutical composition comprising a compound of anyone of claims 1-16 and a pharmaceutical carrier.
 26. The pharmaceuticalcomposition of claim 17 further comprising a second active ingredientselected from the group consisting of an insulin sensitizer, insulinmimetic, sulfonylurea, alpha-glucosidase inhibitor, HMG-CoA reductaseinhibitor, seguestrant cholesterol lowering agent, beta 3 adrenergicreceptor agonist, neuropeptide Y antagonist, phosphodiester V inhibitor,and an alpha 2 adrenergic receptor antagonist.
 27. A method ofpreventing or treating obesity in a mammal comprising the administrationof a therapeutically effective amount of the compound of formula I asrecited in claim
 1. 28. A method of preventing or treating diabetesmellitus in a mammal comprising the administration of a therapeuticallyeffective amount of the compound of formula I as recited in claim
 1. 29.A method of preventing or treating male or female sexual dysfunction ina mammal comprising the administration of a therapeutically effectiveamount of the compound of formula I as recited in claim
 1. 30. Themethod of claim 30, wherein the male sexual dysfunction is erectiledysfunction.
 31. A process for preparing a compound of formula I:

or a pharmaceutically acceptable salts or stereoisomers thereof, wherein—CLL′—(CH₂)_(n)—T is:

wherein R¹⁰ is a CBz or Boc protecting group, hydrogen, (C₁-C₈) alkyl,C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl, C₂-C₈ alkynyl, phenyl, aryl, orheteroaryl; R² is: Hydrogen, C₁-C₈ alkyl, CONHC₁-C₄ alkyl, (D)phenyl,oxo, or (D)C₃-C₇ cycloalkyl, provided that when R² is oxo, R² is on oneof the ring carbon atoms adjacent to Q bearing nitrogen atom; R³ is:phenyl, aryl or thienyl; wherein phenyl, aryl and thienyl are optionallysubstituted with one to three substituents independently selected fromthe group consisting of: cyano, perfluoroalkoxy, halo, C₁-C₈ alkyl,(D)C₃-C₇ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl; R⁴ is hydrogen,C₁-C₈ alkyl, C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl, or (D)phenyl; Q is:—C(R^(a1)) (R^(a2)) (R^(a3)) Wherein R^(a1) is C₁-C₈ alkyl, C₁-C₈alkenyl, C₁-C₈ alkynyl, C₃-Cg alkoxy, (D)C₃-C₇ cycloalkyl, heterocyclic,alkyl heterocyclic, (D)phenyl, aryl, 5 to 7 member benzofused bicyclicring, or heteroaryl, and wherein C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈alkynyl, (D)C₃-C₇ cycloalkyl, heterocyclic, alkyl heterocyclic, phenyl,aryl, 5- or 7-membered benzofused bicyclic ring, and heteroaryl, areeach optionally substituted with one to five substituents independentlyselected from R; R is: hydroxy, halo, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈alkoxy, C₁-C₄ haloalkyl, (D)C₃-C₇ cycloalkyl, (D)aryl, (D)heteroaryl;(D)C(O)C₁-C₄ alkyl, (D)C(O)OC₁-C₄ alkyl, (D)C(O)heteroaryl,(CH₂)_(m)N(R⁸)₂, (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl, (CH₂)_(m)NR⁸SO₂(C₁-C₄alkyl), (D)OC₁-C₄ alkyl, (D)OC(O)C₁-C₄ alkyl, (D)heterocyclic, (D)SC₁-C₄alkyl, or (D)SO₂N(R⁸)₂; wherein C₁-C₈ alkyl, C₁-C₈ alkoxy, C₃-C₇cycloalkyl, phenyl, aryl, heterocyclic, and heteroaryl are optionallysubstituted with one to five substituents independently selected fromR⁸; and provided that when R is halo or hydroxy it is not substituted ona carbon adjacent to a heteroatom; R^(a2) is C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, (D)C₃-C₇ cycloalkyl, phenyl, aryl, (CH₂)_(m)N(R⁸)₂,(CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl, (CH₂)_(m)NR⁸C(O)O C₁-C₄ alkyl,(CH₂)_(m)NR⁸SO₂(C₁-C₄ alkyl), (CH₂)_(m)OC₁-C₄ alkyl, (CH₂)_(m)OC(O)C₁-C₄alkyl, CON(R⁸)₂, wherein for the group or subgroup —N(R⁸)₂, each R⁸ maycombine with the other to form a 5, 6, or 7-membered saturated orunsaturated, optionally substituted nitrogen containing heterocycle;R^(a3) is selected from the group consisting of hydrogen, methyl, ethyland propyl; each R⁸ is independently: hydrogen, oxo, C₁-C₈ alkyl, C₂-C₈alkenyl, (D)C₃-C₇ cycloalkyl, phenyl, aryl or heteroaryl, wherein C₁-C₈alkyl, C₁-C₈ alkenyl, C₃-C₇ cycloalkyl, phenyl, aryl and heteroaryl areoptionally substituted with one to three substituents selected from thegroup consisting of C₁-C₈ alkyl, halo, and hydroxy; provided that thehalo and hydroxy groups are not substituted on a carbon adjacent to aheteroatom; R¹¹ is independently hydrogen, (C₁-C₈)alkyl, or (D)phenyl,or aryl; D is a bond or C₁-C₄ alkyl; y is 1 or 2; m is 1-4; n is 0-8;and p is 0-4; comprising the steps of: a) reacting a compound having astructural formula 1:

with CH₂CH═C(O)OR^(a) wherein R^(a) is hydrogen or C₁-C₈ alkyl and X ishalo, in the presence of a catalyst and a base in a suitable organicsolvent to give the compound of formula 2

b) reductively aminating the compound of formula 2 in the presence ofamine to give a compound of formula 3

c) cyclizing the compound of formula 3 by Michael addition to give acompound of formula 4 or stereoisomers thereof

d) coupling the compound of formula 4 or stereoisomers thereof whereinRa is H, with a compound of formula 5

wherein R^(a) is C₁-C₈ alkyl, to give a compound of formula 6

e) coupling the compound of formula 6 wherein R^(a) is H, with acompound having a structural formula

to afford the compound of formula
 1. 32. The process of claim 31,wherein CH₂CH═C(O)OR^(a) in Step (a) is methylacrylate.
 33. The processof claim 32, wherein the catalyst in Step (a) is selected from the groupconsisting of: Pd(Ph₃P)₂Cl₂, Pd(Ph₃P)₄Cl₂, Pd(Ph₃P)₄, Pd(Ph₃P)₂Cl₂/CuI,Pd(OAc)₂/Ph₃P-Bu₄NBr, Pd(Ph₃P)₄Cl₂/H₂ and Pd(OAc)₂/P(O-tol)₃; andwherein the base in Step (a) is N(R)₃ wherein R is hydrogen or C₁-C₈alkyl.
 34. The process of claim 33, wherein the amine in Step (b) isselected from the group consisting of: benzylamine,alpha-methylbenzylamine and BocNH₂.
 35. The process of claim 34, whereinthe Step (b) further comprises reducing an intermediate imine compoundin the presence of reducing agent, the reducing agent being selectedfrom the group consisting of: NaCNBH₃, Na(OAc)₃BH, NaBH₄/H+, and acombination of Et₃SiH and TFA in CH₃CN or CH₂Cl₂.
 36. The process ofclaim 31, wherein the stereoisomer of compound of formula (7) in Step(c) is a compound of formula 7a


37. The process of claim 36, wherein the compound of formula 7a isprepared by asymmetric hydrogenation of a compound having structuralformula,


38. The process of claim 31, wherein the Michael addition in Step (c) iscarried out under basic workup condition.
 39. The process of claim 31,wherein the Step (e) further comprises deprotecting or protecting of thecompound of formula (4) at NR¹⁰.
 40. A process for preparing a compoundof formula I:

wherein —LL′ (CH₂)_(n)-T is represented by the group:

R² is: Hydrogen, C₁-C₈ alkyl, CONHC₁-C₄ alkyl, (D)phenyl, oxo, or(D)C₃-C₇ cycloalkyl, provided that when R² is oxo, R² is on one of thering carbon atoms adjacent to Q bearing nitrogen atom; R³ is: phenyl,aryl or thienyl; wherein phenyl, aryl and thienyl are optionallysubstituted with one to three substituents independently selected fromthe group consisting of: cyano, perfluoroalkoxy, halo, C₁-C₈ alkyl,(D)C₃-C₇ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl; R⁴ is hydrogen,C₁-C₈ alkyl, C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl, or (D)phenyl; Q is:—C(R^(a1)) (R^(a2)) (R^(a3)) Wherein R^(a1) is C₁-C₈ alkyl, C₁-C₈alkenyl, C₁-C₈ alkynyl, C₃-C₈ alkoxy, (D)C₃-C₇ cycloalkyl, heterocyclic,alkyl heterocyclic, (D)phenyl, aryl, 5 to 7 member benzofused bicyclicring, or heteroaryl, and wherein C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈alkynyl, (D)C₃-C₇ cycloalkyl, heterocyclic, alkyl heterocyclic, phenyl,aryl, 5- or 7-membered benzofused bicyclic ring, and heteroaryl, areeach optionally substituted with one to five substituents independentlyselected from R; R is: hydroxy, halo, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈alkoxy, C₁-C₄ haloalkyl, (D)C₃-C₇ cycloalkyl, (D)aryl, (D)heteroaryl;(D)C(O)C₁-C₄ alkyl, (D)C(O)OC₁-C₄ alkyl, (D)C(O)heteroaryl,(CH₂)_(m)N(R⁸)₂, (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl, (CH₂)_(m)NR⁸SO₂(C₁-C₄alkyl), (D)OC₁-C₄ alkyl, (D)OC(O)C₁-C₄ alkyl, (D)heterocyclic, (D)SC₁-C₄alkyl, or (D)SO₂N(R⁸)₂; wherein C₁-C₈ alkyl, C₁-C₈ alkoxy, C₃-C₇cycloalkyl, phenyl, aryl, heterocyclic, and heteroaryl are optionallysubstituted with one to five substituents independently selected fromR⁸; and provided that when R is halo or hydroxy it is not substituted ona carbon adjacent to a heteroatom; R^(a2) is C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, (D)C₃-C₇ cycloalkyl, phenyl, aryl, (CH₂)_(m)N(R⁸)₂,(CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl, (CH₂)_(m)NR⁸C(O)OC₁-C₄ alkyl,(CH₂)_(m)NR⁸SO₂(C₁-C₄ alkyl), (CH₂)_(m)OC₁-C₄ alkyl, (CH₂)_(m)OC(O)C₁-C₄alkyl, CON(R⁸)₂, wherein for the group or subgroup —N(R⁸)₂, each R⁸ maycombine with the other to form a 5, 6, or 7-membered saturated orunsaturated, optionally substituted nitrogen containing heterocycle;R^(a3) is selected from the group consisting of hydrogen, methyl, ethyland propyl; each R⁸ is independently: hydrogen, oxo, C₁-C₈ alkyl, C₂-C₈alkenyl, (D)C₃-C₇ cycloalkyl, phenyl, aryl or heteroaryl, wherein C₁-C₈alkyl, C₁-C₈ alkenyl, C₃-C₇ cycloalkyl, phenyl, aryl and heteroaryl areoptionally substituted with one to three substituents selected from thegroup consisting of C₁-C₈ alkyl, halo, and hydroxy; provided that thehalo and hydroxy groups are not substituted on a carbon adjacent to aheteroatom; R¹⁰ is hydrogen, (C₁-C₈)alkyl, C₃-C₈ alkenyl, C(O)C₁-C₈alkyl, C₂-C₈ alkynyl, phenyl, aryl, or heteroaryl; R¹¹ is independentlyhydrogen, (C₁-C₈)alkyl, or (D)phenyl, or aryl; D is a bond or C₁-C₄alkyl; y is 1 or 2; m is 1-4; n is 0-8; and p is 0-4; comprising thesteps of: a) esterifying a compound of formula 1 with an alcohol R^(a)OH

to form a compound of formula 2:

2 wherein R^(a) is a group selected from C₁-C₄ alkyl, and (D) phenyl; b)reacting a compound of formula 2 with R¹¹COR¹¹ to form a compound offormula

wherein R¹¹ is independently hydrogen, C₁-C₄ alkyl; c) reacting acompound of formula 3 with an activating group to form a compound offormula 4

wherein A is an activating group; d) deoxygenating the compound offormula 4 by hydrogenation to afford a compound of formula 5

e) optionally reacting the compound of formula 5 wherein HA is anacidic, with an inorganic base to form a compound of formula 6

wherein M is a univalent cation; f) resolving the compound of formula 5or the compound of formula 6 wherein M is hydrogen to afford a chiralcompound of formula 7

wherein Ra′ is H or R^(a); g) coupling the compound of formula 7 with acompound of formula 8

to afford a compound of formula 9:

h) coupling the compound of formula 9 with a compound of formula 10:

to afford a compound of formula I:


41. The process according to claim 40 wherein the esterification isperformed via an acylhalide intermediate formed by rection of compound(1) with thionyl chloride, or oxalylchloride.
 42. The process accordingto claim 40 wherein the activating agent is trifluoromethanesulfonicanhydride to form the triflate.
 43. A process for preparing a compoundof formula I:

wherein —LL′ (CH₂)_(n)—T represents the group:

wherein R¹⁰ is a C₈ or Boc protecting group, hydrogen, (C₁-C₈) alkyl,C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl, C₂-C₈ alkynyl,. phenyl, aryl, orheteroaryl; R² is: Hydrogen, C₁-C₈ alkyl, CONHC₁-C₄ alkyl, (D)phenyl,oxo, or (D)C₃-C₇ cycloalkyl, provided that when R² is oxo, R² is on oneof the ring carbon atoms adjacent to Q bearing nitrogen atom; R³ is:phenyl, aryl or thienyl; wherein phenyl, aryl and thienyl are optionallysubstituted with one to three substituents independently selected fromthe group consisting of: cyano, perfluoroalkoxy, halo, C₁-C₈ alkyl,(D)C₃-C₇ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl; R⁴ is hydrogen,C₁-C₈ alkyl, C₃-C₈ alkenyl, C(O)C₁-C₈ alkyl, or (D)phenyl; Q is:—C(R^(a1)) (R^(a2)) (R^(a3)) Wherein R^(a1) is C₁-C₈ alkyl, C₁-C₈alkenyl, C₁-C₈ alkynyl, C₃-C₈ alkoxy, (D)C₃-C₇ cycloalkyl, heterocyclic,alkyl heterocyclic, (D)phenyl, aryl, 5 to 7 member benzofused bicyclicring, or heteroaryl, and wherein C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈alkynyl, (D)C₃-C₇ cycloalkyl, heterocyclic, alkyl heterocyclic, phenyl,aryl, 5- or 7-membered benzofused bicyclic ring, and heteroaryl, areeach optionally substituted with one to five substituents independentlyselected from R; R is: hydroxy, halo, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈alkoxy, C₁-C₄ haloalkyl, (D)C₃-C₇ cycloalkyl, (D)aryl, (D)heteroaryl;(D)C(O)C₁-C₄ alkyl, (D)C(O)OC₁-C₄ alkyl, (D)C(O)heteroaryl,(CH₂)_(m)N(R⁸ )₂, (CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl, (CH₂)_(m)NR⁸SO₂(C₁-C₄alkyl), (D)OC₁-C₄ alkyl, (D)OC(O)C₁-C₄ alkyl, (D)heterocyclic, (D)SC₁-C₄alkyl, or (D)SO₂N(R⁸)₂; wherein C₁-C₈ alkyl, C₁-C₈ alkoxy, C₃-C₇cycloalkyl, phenyl, aryl, heterocyclic, and heteroaryl are optionallysubstituted with one to five substituents independently selected fromR⁸; and provided that when R is halo or hydroxy it is not substituted ona carbon adjacent to a heteroatom; R^(a2) is C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl, (D)C₃-C₇ cycloalkyl, phenyl, aryl, (CH₂)_(m)N(R⁸)₂,(CH₂)_(m)NR⁸C(O)C₁-C₄ alkyl, (CH₂)_(m)NR⁸C(O)OC₁-C₄ alkyl,(CH₂)_(m)NR⁸SO₂(C₁-C₄ alkyl), (CH₂)_(m)OC₁-C₄ alkyl, (CH₂)_(m)OC(O)C₁-C₄alkyl, CON(R⁸)₂, wherein for the group or subgroup —N(R⁸)₂, each R⁸ maycombine with the other to form a 5, 6, or 7-membered saturated orunsaturated, optionally substituted nitrogen containing heterocycle;R^(a3) is selected from the group consisting of hydrogen, methyl, ethyland propyl; each R⁸ is independently: hydrogen, oxo, C₁-C₈ alkyl, C₂-C₈alkenyl, (D)C₃-C₇ cycloalkyl, phenyl, aryl or heteroaryl, wherein C₁-C₈alkyl, C₁-C₈ alkenyl, C₃-C₇ cycloalkyl, phenyl, aryl and heteroaryl areoptionally substituted with one to three substituents selected from thegroup consisting of C₁-C₈ alkyl, halo, and hydroxy; provided that thehalo and hydroxy groups are not substituted on a carbon adjacent to aheteroatom; R¹ Lis independently hydrogen, (C₁-C₈)alkyl, or (D)phenyl,or aryl; D is a bond or C₁-C₄ alkyl; y is 1 or 2; m is 1-4; n is 0-8;and p is 0-4; comprising the steps of: a) reacting a compound formula 1:

wherein X is halo and R¹¹ is independently, hydrogen or C₁-C₄ alkyl,with CNCH₂CO₂R^(a) wherein R^(a) is C₁-C₈ alkyl, or benzyl to afford acompound of formula 2:

b) protecting the compound of formula 2 to form the compound of formula3:

c) hydrogenating the compound of formula 3 to afford a compound offormula 4:

R^(a′) is hydrogen or R^(a); d) coupling the compound of formula 4wherein R^(a′) is hydrogen with a compound of formula 5:

to afford a compound of formula 6:

e) coupling the compound of formula 6 with a compound of formula 7:

to afford a compound of formula I: